Gene Summary

Gene:CTSD; cathepsin D
Aliases: CPSD, CLN10, HEL-S-130P
Summary:This gene encodes a member of the A1 family of peptidases. The encoded preproprotein is proteolytically processed to generate multiple protein products. These products include the cathepsin D light and heavy chains, which heterodimerize to form the mature enzyme. This enzyme exhibits pepsin-like activity and plays a role in protein turnover and in the proteolytic activation of hormones and growth factors. Mutations in this gene play a causal role in neuronal ceroid lipofuscinosis-10 and may be involved in the pathogenesis of several other diseases, including breast cancer and possibly Alzheimer's disease. [provided by RefSeq, Nov 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cathepsin D
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CTSD (cancer-related)

Wang R, Li J, Yin C, et al.
Role of β-Estradiol in MCF-7 Breast Cancer Cell Line Based on the Bioinformatics Analysis.
Gynecol Obstet Invest. 2019; 84(3):268-276 [PubMed] Related Publications
BACKGROUND: This study aimed to investigate the action mechanism of β-estradiol in MCF-7 breast cancer (BC) cells.
METHODS: The cell samples were sequenced using Hiseq 2000, including 2 MCF-7 controls and 2 samples treated with β-estradiol. Differentially expressed genes (DEGs) were screened using the NOISeq package in R, followed by the functions and pathways analyses using Database for Annotation, Visualization and Integrated Discovery. DEGs associated with β-estradiol were selected using the WbeGestalt software, and the corresponding target miRNAs of these genes were analyzed from different miRNA databases. Additionally, protein-protein interaction network of the drug-associated genes was constructed using Cytoscape.
RESULTS: A total of 1,835 DEGs in BC samples were screened. Thereinto, DEGs associated with BC (17 upregulated and 28 downregulated DEGs) were involved in the regulation of cell proliferation, response to endogenous stimulus, and response to hormone stimulus, while the genes participated in several significant pathways. Cyclin D1, estrogen receptor 1, catechol-O-methyltransferase, and cathepsin D (CTSD; hub genes) were the predicted new genes associated with β-estradiol. Besides, hsa-miR-140-3p was the only target miRNA of CTSD.
CONCLUSION: β-Estradiol may play a key role in contributing to BC progression and metastasis by regulating the expression of the selected genes.

Deng B, Tarhan YE, Ueda K, et al.
Critical Role of Estrogen Receptor Alpha O-Glycosylation by N-Acetylgalactosaminyltransferase 6 (GALNT6) in Its Nuclear Localization in Breast Cancer Cells.
Neoplasia. 2018; 20(10):1038-1044 [PubMed] Free Access to Full Article Related Publications
Alteration of protein O-glycosylation in various human cancers including breast cancer is well known, but molecular roles of their aberrant glycosylations on cancer have not been fully understood. We previously reported critical roles of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6 or GalNAc-T6) that was upregulated in a great majority of breast cancer tissues. Here we further report O-glycosylation of estrogen receptor alpha (ER-α) by GALNT6 and the significant role of its nuclear localization in breast cancer cells. Knockdown of GALNT6 expression in two breast cancer cell lines, T47D and MCF7, in which both ER-α and GALNT6 were highly expressed, by small interfering RNA could significantly attenuate expression of ER-α. Immunocytochemical analysis clearly demonstrated the drastic decrease of ER-α protein in the nucleus of these cancer cells. Accordingly, the downstream genes of the ER-α pathway such as MYC, CCND1, and CTSD were significantly downregulated. We confirmed GALNT6-dependent ER-α O-glycosylation and identified O-glycosylation of S573 in an F domain of ER-α by GALNT6 through LC-MS/MS analysis. We also obtained evidences showing that the glycosylation of ER-α at S573 by GALNT6 is essential for protein stability and nuclear localization of ER-α in breast cancer cells. Furthermore, we designed cell membrane-permeable peptides including the O-glycosylation site and found a significant decrease of the cell viability of breast cancer cells by treatment of these peptides in a GALNT6 expression-dependent manner. Our study suggests that targeting the GALNT6 enzymatic activity as well as the GALNT6/ER-α interaction could be a promising therapeutic approach to ER-α-positive breast cancer patients.

Bannoud N, Carvelli FL, Troncoso M, et al.
Cation-dependent mannose-6-phosphate receptor expression and distribution are influenced by estradiol in MCF-7 breast cancer cells.
PLoS One. 2018; 13(8):e0201844 [PubMed] Free Access to Full Article Related Publications
Cancer cells secrete procathepsin D, and its secretion is enhanced by estradiol. Although alterations in the pro-enzyme intracellular transport have been reported, the mechanism by which it is secreted remains poorly understood. In this work, we have studied the influence of estradiol on the expression and distribution of the cation-dependent mannose-6-phosphate receptor (CD-MPR), which would be a key molecule to ensure the proper localization of the enzyme to lysosomes in breast cancer cells. Immunoblotting studies demonstrated that the expression of CD-MPR is higher in MCF-7 cells, as compared to other breast cancer and non-tumorigenic cells. This expression correlated with high levels of cathepsin D (CatD) in these cells. By immunofluorescence, this receptor mostly co-localized with a Golgi marker in all cell types, exhibiting an additional peripheral labelling in MCF-7 cells. In addition, CD-MPR showed great differences regarding to cation-independent mannose-6-phosphate receptor. On the other hand, the treatment with estradiol induced an increase in CD-MPR and CatD expression and a re-distribution of both proteins towards the cell periphery. These effects were blocked by the anti-estrogen tamoxifen. Moreover, a re-distribution of CD-MPR to plasma membrane-enriched fractions, analyzed by gradient centrifugation, was observed after estradiol treatment. We conclude that, in hormone-responsive breast cancer cells, CD-MPR and CatD are distributed together, and that their expression and distribution are influenced by estradiol. These findings strongly support the involvement of the CD-MPR in the pro-enzyme transport in MCF-7 cells, suggesting the participation of this receptor in the procathepsin D secretion previously reported in breast cancer cells.

Chang BY, Kim DS, Kim HS, Kim SY
Evaluation of estrogenic potential by herbal formula, HPC 03 for
Reproduction. 2018; 155(2):105-115 [PubMed] Related Publications
HPC 03 is herbal formula that consists of extracts from

Bredemeier M, Edimiris P, Mach P, et al.
Gene Expression Signatures in Circulating Tumor Cells Correlate with Response to Therapy in Metastatic Breast Cancer.
Clin Chem. 2017; 63(10):1585-1593 [PubMed] Related Publications
BACKGROUND: Circulating tumor cells (CTCs) are thought to be an ideal surrogate marker to monitor disease progression in metastatic breast cancer (MBC). We investigated the prediction of treatment response in CTCs of MBC patients on the basis of the expression of 46 genes.
METHODS: From 45 MBC patients and 20 healthy donors (HD), 2 × 5 mL of blood was collected at the time of disease progression (TP0) and at 2 consecutive clinical staging time points (TP1 and TP2) to proceed with the AdnaTest
RESULTS: The CTC positivity was defined by the four-gene signature (

Kitazawa S, Nishizawa S, Nakagawa H, et al.
Cancer with low cathepsin D levels is susceptible to vacuolar (H
Cancer Sci. 2017; 108(6):1185-1193 [PubMed] Free Access to Full Article Related Publications
Vacuolar (H

Tanaka Y, Suzuki G, Matsuwaki T, et al.
Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes.
Hum Mol Genet. 2017; 26(5):969-988 [PubMed] Related Publications
Progranulin (PGRN) haploinsufficiency resulting from loss-of-function mutations in the PGRN gene causes frontotemporal lobar degeneration accompanied by TDP-43 accumulation, and patients with homozygous mutations in the PGRN gene present with neuronal ceroid lipofuscinosis. Although it remains unknown why PGRN deficiency causes neurodegenerative diseases, there is increasing evidence that PGRN is implicated in lysosomal functions. Here, we show PGRN is a secretory lysosomal protein that regulates lysosomal function and biogenesis by controlling the acidification of lysosomes. PGRN gene expression and protein levels increased concomitantly with the increase of lysosomal biogenesis induced by lysosome alkalizers or serum starvation. Down-regulation or insufficiency of PGRN led to the increased lysosomal gene expression and protein levels, while PGRN overexpression led to the decreased lysosomal gene expression and protein levels. In particular, the level of mature cathepsin D (CTSDmat) dramatically changed depending upon PGRN levels. The acidification of lysosomes was facilitated in cells transfected with PGRN. Then, this caused degradation of CTSDmat by cathepsin B. Secreted PGRN is incorporated into cells via sortilin or cation-independent mannose 6-phosphate receptor, and facilitated the acidification of lysosomes and degradation of CTSDmat. Moreover, the change of PGRN levels led to a cell-type-specific increase of insoluble TDP-43. In the brain tissue of FTLD-TDP patients with PGRN deficiency, CTSD and phosphorylated TDP-43 accumulated in neurons. Our study provides new insights into the physiological function of PGRN and the role of PGRN insufficiency in the pathogenesis of neurodegenerative diseases.

Haznedaroglu IC, Malkan UY
Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies.
Eur Rev Med Pharmacol Sci. 2016; 20(19):4089-4111 [PubMed] Related Publications
The existence of a local renin-angiotensin system (RAS) specific to the hematopoietic bone marrow (BM) microenvironment had been proposed two decades ago. Most of the RAS molecules including ACE, ACE2, AGT, AGTR1, AGTR2, AKR1C4, AKR1D1, ANPEP, ATP6AP2, CMA1, CPA3, CTSA, CTSD, CTSG, CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, DPP3, EGFR, ENPEP, GPER, HSD11B1, HSD11B2, IGF2R, KLK1, LNPEP, MAS1, MME, NR3C1, NR3C2, PREP, REN, RNPEP, and THOP1 are locally present in the BM microenvironment. Local BM RAS peptides control the hematopoietic niche, myelopoiesis, erythropoiesis, thrombopoiesis and the development of other cellular lineages. Local BM RAS is important in hematopoietic stem cell biology and microenvironment. Angiotensin II regulates the proliferation, differentiation, and engraftment of hematopoietic stem cells. Activation of Mas receptor or ACE2 promotes proliferation of CD34+ cells. BM contains a progenitor that expresses renin throughout development. Angiotensin II attenuates the migration and proliferation of CD34+ Cells and promotes the adhesion of both MNCs and CD34+ cells. Renin cells in hematopoietic organs are precursor B cells. The renin cell requires RBP-J to differentiate. Mutant renin-expressing hematopoietic precursors can cause leukemia. Deletion of RBP-J in the renin-expressing progenitors enriches the precursor B-cell gene programme. Mutant cells undergo a neoplastic transformation, and mice develop a highly penetrant B-cell leukemia with multi-organ infiltration and early death. Many biological conditions during the development and function of blood cells are mediated by RAS, such as apoptosis, cellular proliferation, intracellular signaling, mobilization, angiogenesis, and fibrosis. The aim of this paper is to review recent developments regarding the actions of local BM RAS in the genesis of leukemia and other malignancies molecules.

Huang Y, Chu T, Liao T, et al.
Downregulation of lysosomal and further gene expression characterization in lung cancer patients with bone metastasis.
Artif Cells Nanomed Biotechnol. 2017; 45(4):758-764 [PubMed] Related Publications
Molecular and functional mechanisms of bone metastases were poorly understood. This study was to screen out differentially expressed genes (DEGs) and functional proteins in bone metastases from lung for better understanding of the molecular and functional mechanisms. Our results suggested CTSS, CTSD, MX1, NKX2-1 might play a decisive role in bone metastasis. Collectively, these results demonstrated that bone metastasis from lung cancer would lead to changes in lysosome function, which may affect the decomposition and elimination of old bone matrix, thus affecting bone turnover. In addition, our findings provided new insights into the prediction and treatment of bone metastases.

Go RE, Kim CW, Jeon SY, et al.
Fludioxonil induced the cancer growth and metastasis via altering epithelial-mesenchymal transition via an estrogen receptor-dependent pathway in cellular and xenografted breast cancer models.
Environ Toxicol. 2017; 32(4):1439-1454 [PubMed] Related Publications
Fludioxonil is an antifungal agent used in agricultural applications that is present at measurable amounts in fruits and vegetables. In this study, the effects of fludioxonil on cancer cell viability, epithelial-mesenchymal transition (EMT), and metastasis were examined in MCF-7 clonal variant breast cancer cell (MCF-7 CV cells) with estrogen receptors (ERs). MCF-7 CV cells were cultured with 0.1% DMSO (control), 17β-estradiol (E2; 1 ×10

Guerra E, Cimadamore A, Simeone P, et al.
p53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading.
BMC Cancer. 2016; 16:649 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Traditional prognostic indicators of breast cancer, i.e. lymph node diffusion, tumor size, grading and estrogen receptor expression, are inadequate predictors of metastatic relapse. Thus, additional prognostic parameters appear urgently needed. Individual oncogenic determinants have largely failed in this endeavour. Only a few individual tumor growth drivers, e.g. mutated p53, Her-2, E-cadherin, Trops, did reach some prognostic/predictive power in clinical settings. As multiple factors are required to drive solid tumor progression, clusters of such determinants were expected to become stronger indicators of tumor aggressiveness and malignant progression than individual parameters. To identify such prognostic clusters, we went on to coordinately analyse molecular and histopathological determinants of tumor progression of post-menopausal breast cancers in the framework of a multi-institutional case series/case-control study.
METHODS: A multi-institutional series of 217 breast cancer cases was analyzed. Twenty six cases (12 %) showed disease relapse during follow-up. Relapsed cases were matched with a set of control patients by tumor diameter, pathological stage, tumor histotype, age, hormone receptors and grading. Histopathological and molecular determinants of tumor development and aggressiveness were then analyzed in relapsed versus non-relapsed cases. Stepwise analyses and model structure fitness assessments were carried out to identify clusters of molecular alterations with differential impact on metastatic relapse.
RESULTS: p53, Bcl-2 and cathepsin D were shown to be coordinately associated with unique levels of relative risk for disease relapse. As many Ras downstream targets, among them matrix metalloproteases, are synergistically upregulated by mutated p53, whole-exon sequence analyses were performed for TP53, Ki-RAS and Ha-RAS, and findings were correlated with clinical phenotypes. Notably, TP53 insertion/deletion mutations were only detected in relapsed cases. Correspondingly, Ha-RAS missense oncogenic mutations were only found in a subgroup of relapsing tumors.
CONCLUSIONS: We have identified clusters of specific molecular alterations that greatly improve prognostic assessment with respect to singularly-analysed indicators. The combined analysis of these multiple tumor-relapse risk factors promises to become a powerful approach to identify patients subgroups with unfavourable disease outcome.

Stark MS, Tom LN, Boyle GM, et al.
The "melanoma-enriched" microRNA miR-4731-5p acts as a tumour suppressor.
Oncotarget. 2016; 7(31):49677-49687 [PubMed] Free Access to Full Article Related Publications
We previously identified miR-4731-5p (miR-4731) as a melanoma-enriched microRNA following comparison of melanoma with other cell lines from solid malignancies. Additionally, miR-4731 has been found in serum from melanoma patients and expressed less abundantly in metastatic melanoma tissues from stage IV patients relative to stage III patients. As miR-4731 has no known function, we used biotin-labelled miRNA duplex pull-down to identify binding targets of miR-4731 in three melanoma cell lines (HT144, MM96L and MM253). Using the miRanda miRNA binding algorithm, all pulled-down transcripts common to the three cell lines (n=1092) had potential to be targets of miR-4731 and gene-set enrichment analysis of these (via STRING v9.1) highlighted significantly associated genes related to the 'cell cycle' pathway and the 'melanosome'. Following miR-4731 overexpression, a selection (n=81) of pull-down transcripts underwent validation using a custom qRT-PCR array. These data revealed that miR-4731 regulates multiple genes associated with the cell cycle (e.g. CCNA2, ORC5L, and PCNA) and the melanosome (e.g. RAB7A, CTSD, and GNA13). Furthermore, members of the synovial sarcoma X breakpoint family (SSX) (melanoma growth promoters) were also down-regulated (e.g. SSX2, SSX4, and SSX4B) as a result of miR-4731 overexpression. Moreover, this down-regulation of mRNA expression resulted in ablation or reduction of SSX4 protein, which, in keeping with previous studies, resulted in loss of 2D colony formation. We therefore speculate that loss of miR-4731 expression in stage IV patient tumours supports melanoma growth by, in part; reducing its regulatory control of SSX expression levels.

Kim CW, Go RE, Lee HM, et al.
Cigarette smoke extracts induced the colon cancer migration via regulating epithelial mesenchymal transition and metastatic genes in human colon cancer cells.
Environ Toxicol. 2017; 32(2):690-704 [PubMed] Related Publications
There was considerable evidence that exposure to cigarette smoke is associated with an increased risk for colon cancer. Nevertheless, the mechanism underlying the relationship between cigarette smoking and colon cancer remains unclear. Moreover, there were only a few studies on effects of complexing substance contained in cigarette smoke on colon cancer. Thus, we further investigated whether cigarette smoke extract (CSE) affects the cell cycle, apoptosis and migration of human metastatic colon cancer cells, SW-620. MTT assay revealed that SW-620 cell proliferation was significantly inhibited following treatments with all CSEs, 3R4F, and two-domestic cigarettes, for 9 days in a concentration-dependent manner. Moreover, CSE treatments decreased cyclin D1 and E1, and increased p21 and p27 proteins by Western blot analysis in SW-620 cells. Additionally, the treatment of the cells with CSE contributed to these effects expressing by apoptosis-related proteins. An increased migration or invasion ability of SW-620 cells following CSE treatment was also confirmed by a scratch or fibronectin invasion assay in vitro. In addition, the protein levels of E-cadherin as an epithelial maker were down-regulated, while the mesenchymal markers, N-cadherin, snail, and slug, were up-regulated in a time-dependent manner. A metastatic marker, cathepsin D, was also down-regulated by CSE treatment. Taken together, these results indicate that CSE exposure in colon cancer cells may deregulate the cell growth by altering the expression of cell cycle-related proteins and pro-apoptotic protein, and stimulate cell metastatic ability by altering epithelial-mesenchymal transition (EMT) markers and cathepsin D expression. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 690-704, 2017.

Su S, Zhu X, Lin L, et al.
Lowering Endogenous Cathepsin D Abundance Results in Reactive Oxygen Species Accumulation and Cell Senescence.
Mol Cell Proteomics. 2017; 16(7):1217-1232 [PubMed] Free Access to Full Article Related Publications
Cathepsin D is reportedly to be closely associated with tumor development, migration, and invasion, but its pathological mechanism is not fully elucidated. We aimed to evaluate phenotypic changes and molecular events in response to cathepsin D knockdown. Lowering endogenous cathepsin D abundance (CR) induced senescence in HeLa cells, leading to reduced rate of cell proliferation and impaired tumorigenesis in a mouse model. Quantitative proteomics revealed that compared with control cells (EV), the abundances of several typical lysosomal proteases were decreased in the lysosomal fraction in CR cells. We further showed that cathepsin D knockdown caused increased permeability of lysosomal membrane and reactive oxygen species accumulation in CR cells, and the scavenging of reactive oxygen species by antioxidant was able to rescue cell senescence. Despite the increased reactive oxygen species, the proteomic data suggested a global reduction of redox-related proteins in CR cells. Subsequent analysis indicated that the transcriptional activity of nuclear factor erythroid-related factor 2 (Nrf2), which regulates the expression of groups of antioxidant enzymes, was down-regulated by cathepsin D knockdown. Importantly, Nrf2 overexpression significantly reduced cell senescence. Although transient oxidative stress promoted the accumulation of Nrf2 in the nucleus, we showed that the Nrf2 protein exited nucleus if oxidative stress persisted. In addition, when cathepsin D was transiently knocked down, the cathepsin-related events followed a sequential order, including lysosomal leakage during the early stage, followed by oxidative stress augmentation, and ultimately Nrf2 down-regulation and senescence. Our results suggest the roles of cathepsin D in cancer cells in maintaining lysosomal integrity, redox balance, and Nrf2 activity, thus promoting tumorigenesis. The MS Data are available via ProteomeXchange with identifier PXD002844.

Bhullar KS, Jha A, Rupasinghe HP
Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells.
Chem Biol Interact. 2015; 242:107-22 [PubMed] Related Publications
Anticancer activity of a novel curcumin analog (E)-2-(4-hydroxy-3-methoxybenzylidene)-5-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)cyclopentanone (CUR3d) was studied using a human hepatocellular carcinoma cell line (HepG2). The results showed that CUR3d completely inhibits the tumor cell proliferation in a dose- and time-dependent manner. CUR3d at 100 μmol/L activated the pro-apoptotic caspase-3 along with downregulation of anti-apoptotic BIRC5 and Bcl2. CUR3d treatment controlled the cancer cell growth by downregulating the expression of PI3K/Akt (Akt1, Akt2) pathway along with NF-κB. CUR3d down-regulated the members of epidermal growth receptor family (EGFR, ERBB3, ERBB2) and insulin like growth receptors (IGF1, IGF-1R, IGF2). This correlated with the downregulation of G-protein (RHOA, RHOB) and RAS (ATF2, HRAS, KRAS, NRAS) pathway signaling. CUR3d also arrested cell cycle via inhibition of CDK2, CDK4, CDK5, CDK9, MDM2, MDM4 and TERT genes. Cell cycle essential aurora kinases (AURKα, AURKβ) and polo-like kinases (PLK1, PLK2, PLK3) were also modulated by CUR3d. Topoisomerases (TOP2α, TOP2β), important factors in cancer cell immortality, as well as HIF-1α were downregulated following CUR3d treatment. The expression of protein kinase-C family (PRKC-A, PRKC-D, PRKC-E) was also attenuated by CUR3d. The downregulation of histone deacetylases (Class I, II, IV) and PARP I further strengthened the anticancer efficacy of CUR3d. Downregulation of carcinogenic cathepsins (CTSB, CTSD) and heat shock proteins exhibited CUR3d's potency as a potential immunological adjuvant. Finally, the non-toxic manifestation of CUR3d in healthy liver and lung cells along with downregulation of drug resistant gene ABCC1 further warrant need for advance investigations.

Kim YS, Choi KC, Hwang KA
Genistein suppressed epithelial-mesenchymal transition and migration efficacies of BG-1 ovarian cancer cells activated by estrogenic chemicals via estrogen receptor pathway and downregulation of TGF-β signaling pathway.
Phytomedicine. 2015; 22(11):993-9 [PubMed] Related Publications
BACKGROUND: Epithelial-mesenchymal transition (EMT), which is activated by 17β-estradiol (E2) in estrogen-responsive cancers, is an important process in tumor migration or progression. As typical endocrine disrupting chemicals (EDCs), bisphenol A (BPA) and nonylphenol (NP) have a potential to promote EMT and migration of estrogen-responsive cancers. On the contrary, genistein (GEN) as a phytoestrogen is known to have chemopreventive effects in diverse cancers.
METHODS: In the present study, the effects of BPA and GEN on EMT and the migration of BG-1 ovarian cancer cells and the underlying mechanism were investigated. ICI 182,780, an estrogen receptor (ER) antagonist, was co-treated with E2 or BPA or NP to BG-1 cells to identify the relevance of ER signaling in EMT and migration.
RESULTS: As results, E2 and BPA upregulated the protein expression of vimentin, cathepsin D, and MMP-2, but downregulated the protein expression of E-cadherin via ER signaling pathway, suggesting that E2 and BPA promote EMT and cell migration related gene expressions. However, the increased protein expressions of vimentin, cathepsin D, and MMP-2 by E2, BPA, or NP were reduced by the co-treatment of GEN. In a scratch assay, the migration capability of BG-1 cells was enhanced by E2, BPA, and NP via ER signaling but reversed by the co-treatment of GEN. In the protein expression of SnoN and Smad3, E2, BPA, and NP upregulated SnoN, a negative regulator of TGF-β signaling, and downregulated pSmad3, a transcription factor in the downstream pathway of TGF-β signaling pathway, suggesting that E2, BPA, and NP simultaneously lead to the downregualtion of TGF-β signaling in the process of induction of EMT and migration of BG-1 cells via ER signaling. On the other hand, the co-treatment of GEN reversed the downregulation of TGF-β signaling by estrogenic chemicals.
CONCLUSION: Taken together, GEN suppressed EMT and migration capacities of BG-1 ovarian cancer cells enhanced by E2, BPA, and NP via ER signaling and the downregulation of TGF-β signal.

Go RE, Kim CW, Choi KC
Effect of fenhexamid and cyprodinil on the expression of cell cycle- and metastasis-related genes via an estrogen receptor-dependent pathway in cellular and xenografted ovarian cancer models.
Toxicol Appl Pharmacol. 2015; 289(1):48-57 [PubMed] Related Publications
Fenhexamid and cyprodinil are antifungal agents (pesticides) used for agriculture, and are present at measurable amounts in fruits and vegetables. In the current study, the effects of fenhexamid and cyprodinil on cancer cell proliferation and metastasis were examined. Additionally, the protein expression levels of cyclin D1 and cyclin E as well as cathepsin D were analyzed in BG-1 ovarian cancer cells that express estrogen receptors (ERs). The cells were cultured with 0.1% dimethyl sulfoxide (DMSO; control), 17β-estradiol (E2; 10(-9)M), and fenhexamid or cyprodinil (10(-5)-10(-7)M). Results of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that fenhexamid and cyprodinil increased BG-1 cell proliferation about 1.5 to 2 times similar to E2 (5 times) compared to the control. When the cells were co-treated with ICI 182,780 (10(-8)M), an ER antagonist, the proliferation of pesticide-treated BG-1 cells was decreased to the level of the control. A wound healing assay revealed that the pesticides reduced the disrupted area in the BG-1 cell monolayer similar to E2. Protein levels of cyclin D1 and E as well as cathepsin D were increased by fenhexamid and cyprodinil. This effect was reversed by co-treatment with ICI 182,780. In a xenograft mouse model with transplanted BG-1 cells, cyprodinil significantly increased tumor mass formation about 2 times as did E2 (6 times) compared to the vehicle (0.1% DMSO) over an 80-day period. In contrast, fenhexamid did not promote ovarian tumor formation in this mouse model. Cyprodinil also induced cell proliferation along with the expression of proliferating cell nuclear antigen (PCNA) and cathepsin D in tumor tissues similar to E2. Taken together, these results imply that fenhexamid and cyprodinil may have disruptive effects on ER-expressing cancer by altering the cell cycle- and metastasis-related gene expression via an ER-dependent pathway.

Gemoll T, Epping F, Heinrich L, et al.
Increased cathepsin D protein expression is a biomarker for osteosarcomas, pulmonary metastases and other bone malignancies.
Oncotarget. 2015; 6(18):16517-26 [PubMed] Free Access to Full Article Related Publications
Cancer proteomics provide a powerful approach to identify biomarkers for personalized medicine. Particularly, biomarkers for early detection, prognosis and therapeutic intervention of bone cancers, especially osteosarcomas, are missing. Initially, we compared two-dimensional gel electrophoresis (2-DE)-based protein expression pattern between cell lines of fetal osteoblasts, osteosarcoma and pulmonary metastasis derived from osteosarcoma. Two independent statistical analyses by means of PDQuest® and SameSpot® software revealed a common set of 34 differentially expressed protein spots (p < 0.05). 17 Proteins were identified by mass spectrometry and subjected to Ingenuity Pathway Analysis resulting in one high-ranked network associated with Gene Expression, Cell Death and Cell-To-Cell Signaling and Interaction. Ran/TC4-binding protein (RANBP1) and Cathepsin D (CTSD) were further validated by Western Blot in cell lines while the latter one showed higher expression differences also in cytospins and in clinical samples using tissue microarrays comprising osteosarcomas, metastases, other bone malignancies, and control tissues. The results show that protein expression patterns distinguish fetal osteoblasts from osteosarcomas, pulmonary metastases, and other bone diseases with relevant sensitivities between 55.56% and 100% at ≥87.50% specificity. Particularly, CTSD was validated in clinical material and could thus serve as a new biomarker for bone malignancies and potentially guide individualized treatment regimes.

Zu S, Ma W, Xiao P, et al.
Evaluation of Docetaxel-Sensitive and Docetaxel-Resistant Proteomes in PC-3 Cells.
Urol Int. 2015; 95(1):114-9 [PubMed] Related Publications
OBJECTIVES: Docetaxel was the first drug with proven survival benefit in men with castration-resistant prostate cancer. Acquired resistance to docetaxel precedes fatality in castration-resistant prostate cancer. The aims of this study were to evaluate docetaxel-sensitive and docetaxel-resistant proteomes in PC-3 cells, and to investigate the molecular mechanism of docetaxel-resistant PC-3 cells.
METHODS: Docetaxel-resistant PC-3 cells were developed by docetaxel dose escalation. The global profiling of the protein expression was investigated in docetaxel-sensitive and docetaxel-resistant proteomes in PC-3 cells using 2-dimensional polyacrylamide gel electrophoresis/matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
RESULTS: Forty-nine differential proteins were found in docetaxel-resistant PC-3 cells in comparison with docetaxel-sensitive PC-3 cells. Expression in 29 proteins was upregulated, whereas expression in 20 proteins was downregulated. ATP synthase and galectin-1 were involved in the formation of tumor vessels; calreticulin, cathepsin D, and cofilin were involved in tumor metastasis, and GRP78 (78-kDa glucose-regulated protein) and microtubule-associated protein-6 were involved in drug resistance of tumor.
CONCLUSION: It is suggested that a proteomic expression difference exists between docetaxel-sensitive and docetaxel-resistant PC-3 cells, which would be helpful for further understanding the molecular mechanisms of docetaxel resistance in PC-3 cells.

Kim SH, Hwang KA, Shim SM, Choi KC
Growth and migration of LNCaP prostate cancer cells are promoted by triclosan and benzophenone-1 via an androgen receptor signaling pathway.
Environ Toxicol Pharmacol. 2015; 39(2):568-76 [PubMed] Related Publications
Prostate cancer (PCa) is a global health concern in human males. Recently, it has been known that endocrine-disrupting chemicals (EDCs) may act as an exogenous factor to enhance cancer progression. Triclosan (TCS) and 2,4-dihydroxybenzophenone (BP-1) were reported to bioaccumulate in human bodies through the skin absorption. However, there has been insufficient evidence on the findings that the intervention of EDCs may promote the cancer progression in PCa. In the present study, to verify the risk of TCS and BP-1 to a PCa progression, cancer cell proliferation and migration were investigated in LNCaP PCa cells. TCS and BP-1 increased LNCaP cell proliferative activity and migration as did dihydrotestosterone (DHT). This phenomenon was reversed by the treatment with bicalutamide, a well known AR antagonist, suggesting that TCS and BP-1 acted as a xenoandrogen in LNCaP cells via AR signaling pathway by mimicking the action of DHT. A Western blot assay was performed to identify the alterations in the translational levels of cell growth- and metastasis-related markers, i.e., c-fos, cyclin E, p21, and cathepsin D genes. The expressions of genes related with G1/S transition of cell cycle and metastasis were increased by DHT, TCS, and BP-1, while the expression of p21 protein responsible for cell cycle arrest was reduced by DHT, TCS, and BP-1. Taken together, these results indicated that TCS and BP-1 may enhance the progression of PCa by regulating cell cycle and metastasis-related genes via AR signaling pathway.

Zubor P, Hatok J, Moricova P, et al.
Gene expression profiling of histologically normal breast tissue in females with human epidermal growth factor receptor 2‑positive breast cancer.
Mol Med Rep. 2015; 11(2):1421-7 [PubMed] Related Publications
Gene expression profile‑based taxonomy of breast cancer (BC) has been described as a significant breakthrough in comprehending the differences in the origin and behavior of cancer to allow individually tailored therapeutic approaches. In line with this, we hypothesized that the gene expression profile of histologically normal epithelium (HNEpi) could harbor certain genetic abnormalities predisposing breast tissue cells to develop human epidermal growth factor receptor 2 (HER2)‑positive BC. Thus, the aim of the present study was to assess gene expression in normal and BC tissue (BCTis) from patients with BC in order to establish its value as a potential diagnostic marker for cancer development. An array study evaluating a panel of 84 pathway‑ and disease‑specific genes in HER2‑positive BC and tumor‑adjacent HNEpi was performed using quantitative polymerase chain reaction in 12 patients using microdissected samples from frozen tissue. Common prognostic and predictive parameters of BC were assessed by immunohistochemistry and in situ hybridization. In the BCTis and HNEpi samples of 12 HER2‑positive subjects with BC, the expression of 2,016 genes was assessed. A total of 39.3% of genes were deregulated at a minimal two‑fold deregulation rate and 10.7% at a five‑fold deregulation rate in samples of HNEpi or BCTis. Significant differences in gene expression between BCTis and HNEpi samples were revealed for BCL2L2, CD44, CTSD, EGFR, ERBB2, ITGA6, NGFB, RPL27, SCBG2A1 and SCGB1D2 genes (P<0.05), as well as GSN, KIT, KLK5, SERPINB5 and STC2 genes (P<0.01). Insignificant differences (P<0.07) were observed for CCNA1, CLU, DLC1, GABRP and IL6 genes. The ontological gene analyses revealed that the majority of the deregulated genes in the HNEpi samples were part of the functional gene group directly associated with BC origin and prognosis. Functional analysis showed that the most frequent gene deregulations occurred in genes associated with apoptosis and cell cycle regulation in BCTis samples, and with angiogenesis, regulation of the cell cycle and transcriptional activity in HNEpi samples. The molecular profiling of HNEpi breast tissue revealed gene expression abnormalities that may represent potential markers of increased risk for HER2‑positive malignant transformation of breast tissue, and may be able to be employed as predictors of prognosis.

Varley KE, Gertz J, Roberts BS, et al.
Recurrent read-through fusion transcripts in breast cancer.
Breast Cancer Res Treat. 2014; 146(2):287-97 [PubMed] Free Access to Full Article Related Publications
Read-through fusion transcripts that result from the splicing of two adjacent genes in the same coding orientation are a recently discovered type of chimeric RNA. We sought to determine if read-through fusion transcripts exist in breast cancer. We performed paired-end RNA-seq of 168 breast samples, including 28 breast cancer cell lines, 42 triple negative breast cancer primary tumors, 42 estrogen receptor positive (ER+) breast cancer primary tumors, and 56 non-malignant breast tissue samples. We analyzed the sequencing data to identify breast cancer associated read-through fusion transcripts. We discovered two recurrent read-through fusion transcripts that were identified in breast cancer cell lines, confirmed across breast cancer primary tumors, and were not detected in normal tissues (SCNN1A-TNFRSF1A and CTSD-IFITM10). Both fusion transcripts use canonical splice sites to join the last splice donor of the 5' gene to the first splice acceptor of the 3' gene, creating an in-frame fusion transcript. Western blots indicated that the fusion transcripts are translated into fusion proteins in breast cancer cells. Custom small interfering RNAs targeting the CTSD-IFITM10 fusion junction reduced expression of the fusion transcript and reduced breast cancer cell proliferation. Read-through fusion transcripts between adjacent genes with different biochemical functions represent a new type of recurrent molecular defect in breast cancer that warrant further investigation as potential biomarkers and therapeutic targets. Both breast cancer associated fusion transcripts identified in this study involve membrane proteins (SCNN1A-TNFRSF1A and CTSD-IFITM10), which raises the possibility that they could be breast cancer-specific cell surface markers.

Li M, Guo J, Gao W, et al.
Bisphenol AF-induced endogenous transcription is mediated by ERα and ERK1/2 activation in human breast cancer cells.
PLoS One. 2014; 9(4):e94725 [PubMed] Free Access to Full Article Related Publications
Bisphenol AF (BPAF)-induced transcriptional activity has been evaluated by luciferase reporter assay. However, the molecular mechanism of BPAF-induced endogenous transcription in human breast cancer cells has not been fully elucidated. In the present study, we investigated the effect and mechanism of BPAF-induced endogenous transcription detected by real-time PCR in human breast cancer cells. We found that BPAF stimulated transcription of estrogen responsive genes, such as trefoil factor 1 (TFF1), growth regulation by estrogen in breast cancer 1 (GREB1) and cathepsin D (CTSD), through dose-dependent and time-dependent manners in T47D and MCF7 cells. Gene-silencing of ERα, ERβ and G protein-coupled estrogen receptor 1 (GPER) by small interfering RNA revealed that BPAF-induced endogenous transcription was dependent on ERα and GPER, implying both genomic and nongenomic pathways might be involved in the endogenous transcription induced by BPAF. ERα-mediated gene transcription was further confirmed by inhibition of ER activity using ICI 182780 in ERα-positive T47D and MCF7 cells as well as overexpression of ERα in ERα-negative MDA-MB-231 breast cancer cells. Moreover, we utilized Src tyrosine kinase inhibitor PP2 and two MEK inhibitors PD98059 and U0126 to elucidate the rapid nongenomic activation of Src/MEK/ERK1/2 cascade on endogenous transcription. Our data showed that BPAF-induced transcription could be significantly blocked by PP2, PD98059 and U0126, suggesting activation of ERK1/2 was also required to regulate endogenous transcription. Taken together, these results indicate that BPAF-induced endogenous transcription of estrogen responsive genes is mediated through both genomic and nongenomic pathways involving the ERα and ERK1/2 activation in human breast cancer cells.

Saenger Y, Magidson J, Liaw B, et al.
Blood mRNA expression profiling predicts survival in patients treated with tremelimumab.
Clin Cancer Res. 2014; 20(12):3310-8 [PubMed] Related Publications
PURPOSE: Tremelimumab (ticilimumab, Pfizer), is a monoclonal antibody (mAb) targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Ipilimumab (Yervoy, BMS), another anti-CTLA-4 antibody, is approved by the U.S. Federal Drug Administration (FDA). Biomarkers are needed to identify the subset of patients who will achieve tumor control with CTLA-4 blockade.
EXPERIMENTAL DESIGN: Pretreatment peripheral blood samples from 218 patients with melanoma who were refractory to prior therapy and receiving tremelimumab in a multicenter phase II study were measured for 169 mRNA transcripts using reverse transcription polymerase chain reaction (RT-PCR). A two-class latent model yielded a risk score based on four genes that were highly predictive of survival (P < 0.001). This signature was validated in an independent population of 260 treatment-naïve patients with melanoma enrolled in a multicenter phase III study of tremelimumab.
RESULTS: Median follow-up was 297 days for the training population and 386 days for the test population. Expression levels of the 169 genes were closely correlated across the two populations (r = 0.9939). A four-gene model, including cathepsin D (CTSD), phopholipase A2 group VII (PLA2G7), thioredoxin reductase 1 (TXNRD1), and interleukin 1 receptor-associated kinase 3 (IRAK3), predicted survival in the test population (P = 0.001 by log-rank test). This four-gene model added to the predictive value of clinical predictors (P < 0.0001).
CONCLUSIONS: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral blood are predictive of survival in patients with melanoma treated with tremelimumab. Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy.

Daniel AR, Gaviglio AL, Knutson TP, et al.
Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes.
Oncogene. 2015; 34(4):506-15 [PubMed] Free Access to Full Article Related Publications
Progesterone and estrogen are important drivers of breast cancer proliferation. Herein, we probed estrogen receptor-α (ER) and progesterone receptor (PR) cross-talk in breast cancer models. Stable expression of PR-B in PR-low/ER+ MCF7 cells increased cellular sensitivity to estradiol and insulin-like growth factor 1 (IGF1), as measured in growth assays performed in the absence of exogenous progestin; similar results were obtained in PR-null/ER+ T47D cells stably expressing PR-B. Genome-wide microarray analyses revealed that unliganded PR-B induced robust expression of a subset of estradiol-responsive ER target genes, including cathepsin-D (CTSD). Estradiol-treated MCF7 cells stably expressing PR-B exhibited enhanced ER Ser167 phosphorylation and recruitment of ER, PR and the proline-, glutamate- and leucine-rich protein 1 (PELP1) to an estrogen response element in the CTSD distal promoter; this complex co-immunoprecipitated with IGF1 receptor (IGFR1) in whole-cell lysates. Importantly, ER/PR/PELP1 complexes were also detected in human breast cancer samples. Inhibition of IGF1R or phosphoinositide 3-kinase blocked PR-B-dependent CTSD mRNA upregulation in response to estradiol. Similarly, inhibition of IGF1R or PR significantly reduced ER recruitment to the CTSD promoter. Stable knockdown of endogenous PR or onapristone treatment of multiple unmodified breast cancer cell lines blocked estradiol-mediated CTSD induction, inhibited growth in soft agar and partially restored tamoxifen sensitivity of resistant cells. Further, combination treatment of breast cancer cells with both onapristone and IGF1R tyrosine kinase inhibitor AEW541 was more effective than either agent alone. In summary, unliganded PR-B enhanced proliferative responses to estradiol and IGF1 via scaffolding of ER-α/PELP1/IGF1R-containing complexes. Our data provide a strong rationale for targeting PR in combination with ER and IGF1R in patients with luminal breast cancer.

Sun Z, Dong J, Zhang S, et al.
Identification of chemoresistance-related cell-surface glycoproteins in leukemia cells and functional validation of candidate glycoproteins.
J Proteome Res. 2014; 13(3):1593-601 [PubMed] Related Publications
Chemoresistance remains the most significant obstacle to successful chemotherapy for leukemia, and its exact mechanism is still unknown. In this work, we used the cell-surface capturing method together with quantitative proteomics to investigate differences in the glycoproteomes of adriamycin-sensitive and adriamycin-resistant leukemia cells. Two quantitative methods, isotopic dimethyl labeling and SWATH, were used to quantify glycoproteins, and 35 glycoproteins were quantified by both methods. High correlation was observed between the glycoproteins quantified by the above two methods, and 15 glycoproteins displayed a consistent significant change trend in both sets of quantitative results. These 15 proteins included classical multidrug resistance-related glycoproteins such as ABCB1 as well as a set of novel glycoproteins that have not previously been reported to be associated with chemoresistance in leukemia cells. Further validation with quantitative real-time PCR and Western blotting confirmed the proteomic screening results. Subsequent functional experiments based on RNA interference technology showed that CTSD, FKBP10, and SLC2A1 are novel genes that participate in the acquisition and maintenance of the adriamycin-resistant phenotype in leukemia cells.

Nait Achour T, Sentis S, Teyssier C, et al.
Transcriptional repression of estrogen receptor α signaling by SENP2 in breast cancer cells.
Mol Endocrinol. 2014; 28(2):183-96 [PubMed] Free Access to Full Article Related Publications
Estrogen receptors (ERs) are ligand-activated transcription factors involved in many physiological and pathological processes, including breast cancer. Their activity is fine-tuned by posttranslational modifications, notably sumoylation. In the present study, we investigated the role of the small ubiquitin-related modifier (SUMO) protease, SUMO1/sentrin/suppressor of Mif 2-specific peptidase 2 (SENP2), in the regulation of ERα activity. We first found SENP2 to significantly repress estradiol-induced transcriptional activity in breast cancer cells (MCF7 and T47D). This effect was observed with a reporter plasmid and on endogenous genes such as TFF1 and CTSD, which were shown to recruit SENP2 in chromatin immunoprecipitation experiments. Using glutathione S-transferase pull-down, coimmunoprecipitation and proximity ligation assays, SENP2 was found to interact with ERα and this interaction to be mediated by the amino-terminal region of the protease and the hinge region of the receptor. Interestingly, we demonstrated that ERα repression by SENP2 is independent of its SUMO protease activity and requires a transcriptional repressive domain located in the amino-terminal end of the protease. Using small interfering RNA assays, we evidenced that this domain recruits the histone deacetylase 3 (HDAC3), to be fully active. Furthermore, using both overexpression and knockdown strategies, we showed that SENP2 robustly represses estrogen-dependent and independent proliferation of MCF7 cells. We provided evidence that this effect requires both the proteolytic and transcriptional activities of SENP2. Altogether, our study unravels a new property for a SUMO protease and identifies SENP2 as a classical transcription coregulator.

Cui Y, Xie S, Luan J, et al.
Quantitative proteomics and protein network analysis of A549 lung cancer cells affected by miR-206.
Biosci Trends. 2013; 7(6):259-63 [PubMed] Related Publications
MiR-206 acts as a potential tumor suppressor during carcinogenesis and a regulatory factor in osteoblasts differentiation, but its modulatory mechanism remains unclear. In this study, we used a quantitative proteomics method, difference gel electrophoresis (DIGE), to profile the protein variation in A549 lung cancer cells with and without miR- 206 transfection. We identified a total of 17 differently expressed proteins including 5 up-regulated and 12 down-regulated proteins affected by miR-206 in A549 cells. We further constructed a protein network linked 17 differently expressed proteins with 106 computationally predicted miR-206 targets, and identified 8 "hub" genes (CALR, CTSD, ENO1, HSPA5, CDC42, HSPD1, POLA1, and SMARCA4) within the network, which may represent important miR-206 functional gene targets. In conclusion, in this study, we identified several candidate functional target genes for miR-206, which is helpful to further explore its mechanisms during carcinogenesis and osteogenesis, and we also proposed a novel proteomic strategy to identify functionally important gene targets for microRNA.

Mikulová V, Cabiňaková M, Janatková I, et al.
Detection of circulating tumor cells during follow-up of patients with early breast cancer: Clinical utility for monitoring of therapy efficacy.
Scand J Clin Lab Invest. 2014; 74(2):132-42 [PubMed] Related Publications
INTRODUCTION: Circulating tumor cells (CTCs) detection prior to and during therapy is considered as an independent and strong prognostic marker. The present study was designed to isolate and characterize CTCs in peripheral blood of an early breast cancer (BC) patient as a biomarker for monitoring treatments efficacy.
MATERIALS AND METHODS: In total, 54 early breast cancer patients undergoing neoadjuvant and/or adjuvant chemotherapy regimens were enrolled into a prospective study. CTC detection in blood was performed by AdnaTest BreastCancer(™) (AdnaGen AG, Germany), which is based on the detection of EpCAM, HER2 and MUC1 specific transcripts in enriched CTC-lysates. Additionally, cDNA from isolated CTCs and PBMC was used for qPCR gene expression analysis of TOP1, TOP2A, CTSD, ST6, CK19 and reference gene actin.
RESULTS: We found that CTCs can be detected in the peripheral blood of approximately 31% of early stage breast cancer patients. The presence of CTCs was detected in 36% ER positive, 32% PR positive and 30% HER2 positive patients. We found no correlation between CTCs and tumor size, tumor grade, histological grade and receptor status. Only 7% of all patients remained CTCs positive after adjuvant therapy. Gene expression analysis revealed a particular heterogeneity of the studied genes.
CONCLUSIONS: In conclusion, CTC detection may be a promising early marker of disease progression potentially enhancing the difficult therapeutic decisions. Further studies should, however, clearly demonstrate its utility for both the prediction of outcome and monitoring the effect of treatment.

Crabtree D, Dodson M, Ouyang X, et al.
Over-expression of an inactive mutant cathepsin D increases endogenous alpha-synuclein and cathepsin B activity in SH-SY5Y cells.
J Neurochem. 2014; 128(6):950-61 [PubMed] Free Access to Full Article Related Publications
Parkinson's disease is a neurodegenerative movement disorder. The histopathology of Parkinson's disease comprises proteinaceous inclusions known as Lewy bodies, which contains aggregated α-synuclein. Cathepsin D (CD) is a lysosomal protease previously demonstrated to cleave α-synuclein and decrease its toxicity in both cell lines and mouse brains in vivo. Here, we show that pharmacological inhibition of CD, or introduction of catalytically inactive mutant CD, resulted in decreased CD activity and increased cathepsin B activity, suggesting a possible compensatory response to inhibition of CD activity. However, this increased cathepsin B activity was not sufficient to maintain α-synuclein degradation, as evidenced by the accumulation of endogenous α-synuclein. Interestingly, the levels of LC3, LAMP1, and LAMP2, proteins involved in autophagy-lysosomal activities, as well as total lysosomal mass as assessed by LysoTracker flow cytometry, were unchanged. Neither autophagic flux nor proteasomal activities differs between cells over-expressing wild-type versus mutant CD. These observations point to a critical regulatory role for that endogenous CD activity in dopaminergic cells in α-synuclein homeostasis which cannot be compensated for by increased Cathepsin B. These data support the potential need to enhance CD function in order to attenuate α-synuclein accumulation as a therapeutic strategy against development of synucleinopathy.

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