Gene Summary

Gene:PDCD5; programmed cell death 5
Aliases: TFAR19
Summary:This gene encodes a protein that is upregulated during apoptosis where it translocates rapidly from the cytoplasm to the nucleus. The encoded protein may be an important regulator of K(lysine) acetyltransferase 5 (a protein involved in transcription, DNA damage response and cell cycle control) by inhibiting its proteasome-dependent degradation. Pseudogenes have been identified on chromosomes 5 and 12 [provided by RefSeq, Dec 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:programmed cell death protein 5
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: PDCD5 (cancer-related)

Wang C, Li JK, Li HZ, Gong HD
The importance of expressing PDCD4 and PDCD5 anti-oncogenes in glioma.
J Biol Regul Homeost Agents. 2018 May-Jun; 32(3):731-736 [PubMed] Related Publications
Glioma is the most common malignant tumor of the brain, which is difficult to be completely resected. The recurrence and mortality rates are high and the prognosis is poor. The aim of this study was to investigate the expression of anti-oncogene programmed cell death 4 (PDCD4) and programmed cell death 5 (PDCD5) in glioma and their influence on the progression of the disease in order to provide new therapeutic approaches. Reverse transcription polymerase chain reaction (RT-PCR) analysis was used to investigate PDCD4 mRNA and PDCD5 mRNA expression in 66 glioma patients who served as the study group and 22 patients who suffered from craniocerebral injuries or hematencephalon who were used as controls. The experimental group was divided into a low malignant group (tumors grade I - II) and a high malignant group (tumor grades III-IV). The PDCD4 mRNA and PDCD5 mRNA expression in the experimental group was 0.545±0.202 and 0.687±0.174 and in the control group was 0.942±0.131 and 0.868 ± 0.190, respectively (P less than 0.05). The PDCD4 mRNA and PDCD5 mRNA expressions in the low malignant group were 0.628±0.240 and 0.750±0.198, respectively, and in the high malignant group were 0.464±0.185 and 0.553±0.170, respectively (P less than 0.05). The results showed a downregulation of PDCD4 mRNA and PDCD5 mRNA expression in the experimental group compared with the control group. This downregulation was correlated with the pathological grade of glioma. In the high malignant group the PDCD4 mRNA and PDCD5 mRNA expressions were significantly decreased compared with the low malignant group and the control group. PDCD4 mRNA and PDCD5 mRNA expressions are promising targets for the diagnosis and treatment of glioma.

Qiao F, Gong P, Song Y, et al.
Downregulated PITX1 Modulated by MiR-19a-3p Promotes Cell Malignancy and Predicts a Poor Prognosis of Gastric Cancer by Affecting Transcriptionally Activated PDCD5.
Cell Physiol Biochem. 2018; 46(6):2215-2231 [PubMed] Related Publications
BACKGROUND/AIMS: PITX1 has been identified as a potential tumor-suppressor gene in several malignant tumors. The molecular mechanism underlying PITX1, particularly its function as a transcription factor regulating gene expression during tumorigenesis, is still poorly understood.
METHODS: The expression level and location of PITX1 were determined by quantitative reverse transcription PCR (qRT-PCR) and immunohistochemical staining in gastric cancer (GC). The effect of PITX1 on the GC cell proliferation and tumorigenesis was analyzed in vitro and in vivo. To explore how PITX1 suppresses cell proliferation, we used PITX1-ChIP-sequencing to measure genome-wide binding sites of PITX1 and assessed global function associations based on its putative target genes. ChIP-PCR, electrophoretic mobility shift assay, and promoter reporter assays examined whether PITX1 bound to PDCD5 and regulated its expression. The function of PDCD5 in GC cell apoptosis was further examined in vitro and in vivo. The relationship between the PITX1 protein level and GC patient prognosis was evaluated by the Kaplan-Meier estimator. Meanwhile, the expression level of miR-19a-3p, which is related to PITX1, was also detected by luciferase reporter assay, qRT-PCR, and western blotting.
RESULTS: The expression level of PITX1 was decreased in GC tissues and cell lines. Elevated PITX1 expression significantly suppressed the cell proliferation of GC cells and tumorigenesis in vitro and in vivo. PITX1 knockdown blocked its inhibition of GC cell proliferation. PITX1 bound to whole genome-wide sites, with these targets enriched on genes with functions mainly related to cell growth and apoptosis. PITX1 bound to PDCD5, an apoptosis-related gene, during tumorigenesis, and cis-regulated PDCD5 expression. Increased PDCD5 expression in GC cells not only induced GC cell apoptosis, but also suppressed GC cell growth in vitro and in vivo. Moreover, PITX1 expression was regulated by miR-19a-3p. More importantly, a decreased level of PITX1 protein was correlated with poor GC patient prognosis.
CONCLUSION: Decreased expression of PITX1 predicts shorter overall survival in GC patients. As a transcriptional activator, PITX1 regulates apoptosis-related genes, including PDCD5, during gastric carcinogenesis. These data indicate PDCD5 to be a novel and feasible therapeutic target for GC.

Cheng Q, Liu L, Fu Y, et al.
RhPDCD5 combined with dexamethasone increases antitumor activity in multiple myeloma partially via inhibiting the Wnt signalling pathway.
Clin Exp Pharmacol Physiol. 2018; 45(2):140-145 [PubMed] Related Publications
Multiple myeloma (MM) is one of the most common hematological malignancies and characterized by the clonal accumulation of malignant plasma cells. Significant progress has been made in MM treatment recently, while MM still remains incurable. Our previous studies showed that the recombined human programmed cell death 5 (rhPDCD5) can promote MM apoptosis induced by dexamethasone (Dex). Here, we expanded the findings by showing that the rhPDCD5 alone could not induce an obvious growth inhibition of U266 cells (a MM cell line). Of note, with the combination of dexamethasone (Dex), the growth of MM cells was significantly inhibited and accompanied with the cell cycle arrest in G0/G1. For mechanism study, we found that the combination treatment of rhPDCD5 plus Dex downregulated the mRNA and protein expressions of Wnt effectors including β-catenin, β-catenin (Ser675), TCF4, survivin and c-Myc when compared to Dex only. Moreover, the activation of WNT pathway induced by LiCl can also be inhibited by this combination treatment. Taken together, our study demonstrated that the combination of rhPDCD5 and Dex can suppress the proliferation of multiple myeloma cells partially via inhibiting the WNT signalling pathway.

Wang W, Song XW, Zhao CH
Roles of programmed cell death protein 5 in inflammation and cancer (Review).
Int J Oncol. 2016; 49(5):1801-1806 [PubMed] Related Publications
PDCD5 (programmed cell death 5) is an apoptosis related gene cloned in 1999 from a human leukemic cell line. PDCD5 protein containing 125 amino acid (aa) residues sharing significant homology to the corresponding proteins of species. Decreased expression of PDCD5 has been found in many human tumors, including breast, gastric cancer, astrocytic glioma, chronic myelogenous leukemia and hepatocellular carcinoma. In recent years, increased number of studies have shown the functions and mechanisms of PDCD5 protein in cancer cells, such as paraptosis, cell cycle and immunoregulation. In the present review, we provide a comprehensive review on the role of PDCD5 in cancer tissues and cells. This review summarizes the recent studies of the roles of PDCD5 in inflammation and cancer. We mainly focus on discoveries related to molecular mechanisms of PDCD5 protein. We also discuss some discrepancies between the current studies. Overall, the current available data will open new perspectives for a better understanding of PDCD5 in cancer.

Zarea M, Mohammadian Bajgiran A, Sedaghati F, et al.
Diagnostic investigations of DKK-1 and PDCD5 expression levels as independent prognostic markers of human chondrosarcoma.
IUBMB Life. 2016; 68(7):597-601 [PubMed] Related Publications
In this study, we investigated the expression levels of Dickkopf-1 (DKK-1) and programmed cell death 5 (PDCD5) by using quantitative real-time PCR and immunohistochemistry in patients with chondrosarcoma. The DKK-1 mRNA levels were significantly higher in chondrosarcoma when compared with the corresponding nontumor tissues (mean ± SD: 4.23 ± 1.54; 1.54 ± 0.87; P = 0.001). PDCD5 mRNA levels were remarkably deceased in tumor tissues when compared with corresponding nontumor tissues (mean ± SD: 1.94 ± 0.73; 5.42 ± 1.73; P = 0.001). The high and moderate DKK-1 expressions were observed for 60% of chondrosarcoma samples in comparison with 27.5% of corresponding nontumor tissues (P  =  0.001). Moreover, low expression of PDCD5 was found in 67.5% of the tumor tissues when compared with the nontumor tissues (32.5%; P = 0.002). The results of this study showed that high DKK-1 expression levels were strongly related to MSTS stage (P = 0.011) and the advancement of histological grade (P < 0.001). Furthermore, the PDCD5 expression levels were correlated with histological grade (P < 0.001), MSTS stage (P = 0.016), and distant metastasis (P = 0.001). Kaplan-Meier survival and log-rank survival showed that patients with high DKK-1 levels and low PDCD5 levels were correlated with shorter overall survival (log-rank test P < 0.001). PDCD5 levels, histological grade, and tumor stage were independent predictors of overall survival. In conclusion, DKK-1 and PDCD5 can be independent predictors of overall survival in patients suffering from chondrosarcoma. © 2016 IUBMB Life, 68(7):597-601, 2016.

Feng W, Fu Y, Zhang Y, et al.
Establishment of stable multiple myeloma cell line with overexpressed PDCD5 and its proapoptosis mechanism.
Int J Clin Exp Pathol. 2015; 8(9):10635-43 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The transfected multiple myeloma cell line showing a stable doxycycline (DOX)-induced expression of PDCD5 was established. PDCD5 overexpression in the transfected cell line was analyzed for its effect on the dexamethasone (DXM)-induced apoptosis along with a discussion on the mechanism.
METHODS: (1) Lentiviral plasmid was used for the transfection of PDCD5 gene into the multiple myeloma cells. The screening was done by applying puromycin, and PDCD5 expression was induced by DOX. Real-time fluorescence quantitative PCR and Western Blot were performed to detect the expression levels of the target gene in the stable transfection group and the empty vector group; (2) The cell apoptosis rates of stable transfection group, blank group and empty vector group were measured by Annexin-APC/PI double staining flow cytometry; (3) Real-time fluorescence quantitative PCR and Western Blot were carried out to detect the expression levels of survivin, casepase-3 and Bcl-2 genes and proteins.
RESULTS: PDCD5 expression was significantly increased in the stably tranfected multiple myeloma cells compared with blank group and empty vector group. The cells in the transfection group were more sensitive to DXM, and the proportion of apoptotic cells was obviously higher than that of the blank group and the empty vector group (P<0.05). Survivin and Bcl-2 were considerably downregulated in U266/PDCD5 cells and combined DXM group than in the single agent group. However, caspase-3 was significantly upregulated.
CONCLUSION: Multiple myeloma cell line transfected with endogenous PDCD5 gene was established. The endogenous PDCD5 overexpression accelerated the cell apoptosis under DXM induction. The proapoptotic action of PDCD5 gene had the effect of activating casepase-3 and downregulating survivin and Bcl-2, which further promoted the apoptosis of multiple myeloma cells.

Choi HK, Choi Y, Park ES, et al.
Programmed cell death 5 mediates HDAC3 decay to promote genotoxic stress response.
Nat Commun. 2015; 6:7390 [PubMed] Free Access to Full Article Related Publications
The inhibition of p53 activity by histone deacetylase 3 (HDAC3) has been reported, but the precise molecular mechanism is unknown. Here we show that programmed cell death 5 (PDCD5) selectively mediates HDAC3 dissociation from p53, which induces HDAC3 cleavage and ubiquitin-dependent proteasomal degradation. Casein kinase 2 alpha phosphorylates PDCD5 at Ser-119 to enhance its stability and importin 13-mediated nuclear translocation of PDCD5. Genetic deletion of PDCD5 abrogates etoposide (ET)-induced p53 stabilization and HDAC3 cleavage, indicating an essential role of PDCD5 in p53 activation. Restoration of PDCD5(WT) in PDCD5(-/-) MEFs restores ET-induced HDAC3 cleavage. Reduction of both PDCD5 and p53, but not reduction of either protein alone, significantly enhances in vivo tumorigenicity of AGS gastric cancer cells and correlates with poor prognosis in gastric cancer patients. Our results define a mechanism for p53 activation via PDCD5-dependent HDAC3 decay under genotoxic stress conditions.

Park SY, Choi HK, Choi Y, et al.
Deubiquitinase OTUD5 mediates the sequential activation of PDCD5 and p53 in response to genotoxic stress.
Cancer Lett. 2015; 357(1):419-427 [PubMed] Related Publications
Programmed cell death 5 (PDCD5) positively regulates p53-mediated apoptosis and rapidly accumulates upon DNA damage. However, the underlying mechanism of PDCD5 upregulation during the DNA damage response remains unknown. Here, we found that OTU deubiquitinase 5 (OTUD5) was bound to PDCD5 in response to etoposide treatment and increased the stability of PDCD5 by mediating deubiquitination of PDCD5 at Lys-97/98. Overexpression of OTUD5 efficiently enhanced the activation of both PDCD5 and p53. Conversely, PDCD5 knockdown greatly attenuated the effect of OTUD5 on p53 activation. In addition, when OTUD5 was depleted, PDCD5 failed to facilitate p53 activation, demonstrating an essential role for the PDCD5-OTUD5 network in p53 activation. Importantly, we found that OTUD5-dependent PDCD5 stabilization was required for sequential activation of p53 in response to genotoxic stress. The sequential activation of PDCD5 and p53 was abrogated by knockdown of OTUD5. Finally, impairment of the genotoxic stress response upon PDCD5 ablation was substantially rescued by reintroducing PDCD5(WT) but not PDCD5(E94D) (defective for OTUD5 interaction) or PDCD5(E16D) (defective for p53 interaction). Together, our findings have uncovered an apoptotic signaling cascade linking PDCD5, OTUD5, and p53 during genotoxic stress responses.

Cui X, Choi HK, Choi YS, et al.
DNAJB1 destabilizes PDCD5 to suppress p53-mediated apoptosis.
Cancer Lett. 2015; 357(1):307-315 [PubMed] Related Publications
Although PDCD5 promotes p53-mediated apoptosis in various cancers, little is known about PDCD5 regulation. We recently found that DNAJB1 interacts with PDCD5 and induces the ubiquitin-dependent proteasomal degradation of PDCD5, thereby inhibiting p53-mediated apoptosis. To investigate these novel roles for PDCD5 and DNAJB1, we performed DNAJB1 mapping with PDCD5. PDCD5 specifically binds to the DNAJB1-D5 domain (Δ180-210), which was found to be essential for the stabilization of PDCD5. Further study showed that DNAJB1 post-translationally regulates PDCD5 stability. DNAJB1 ubiquitinated PDCD5 via a ubiquitin-mediated pathway. In human lung A549 cancer cells, DNAJB1 promoted the ubiquitination and degradation of PDCD5 and inhibited p53 activation. However, DNAJB1 knockdown in A549 cells increased the etoposide-induced activation of the p53-mediated apoptosis pathway and repressed cancer cell growth. Because this function was p53 dependent, DNAJB1 depletion increased the expression of p53-targeted apoptosis genes. In conclusion, we screened a novel PDCD5-associating protein, DNAJB1, by yeast two-hybrid screening and provided evidences that DNAJB1 targets PDCD5 to suppress p53-dependent apoptosis of cancer cells. Thus, we identified DNAJB1 as a negative regulator of PDCD5-mediated apoptosis and found that the apoptosis network of PDCD5 regulates cancer cell death.

Zhang Y, Liu H, Cui M, et al.
Effect of the HBV whole-X gene on the expression of hepatocellular carcinoma associated proteins.
J Microbiol Immunol Infect. 2016; 49(3):335-43 [PubMed] Related Publications
BACKGROUND: The hepatitis B virus (HBV) pre-X gene resides upstream of the HBV X gene, and together they form the HBV whole-X gene. Although it has been evident that the HBV whole-X protein is involved in the development of hepatocellular carcinoma, its biological role and molecular mechanism remain largely unknown.
METHODS: In this study, we subcloned the HBV whole-X gene and constructed a HBV whole-X expressing vector. After transfection of the HBV whole-X gene into HL-7702 cells, the profile of the differential cellular protein composition in the cells was analyzed by using two-dimensional electrophoresis coupled to matrix-assisted laser desorption/ionization-time of flight mass spectrometry.
RESULTS: The results showed that 18 major proteins were differentially expressed in the cells transfected with or without the HBV whole-X gene. The expression of these genes was further confirmed by reverse transcription-polymerase chain reaction and Western blot analysis.
CONCLUSION: Our findings provide a new insight into the investigation of the pathological role that the HBV whole-X gene plays in the development of hepatocellular carcinoma and may lead to the design of novel strategies for the treatment of this disease.

Essers PB, Klasson TD, Pereboom TC, et al.
The von Hippel-Lindau tumor suppressor regulates programmed cell death 5-mediated degradation of Mdm2.
Oncogene. 2015; 34(6):771-9 [PubMed] Related Publications
Functional loss of the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL), which is part of an E3-ubiquitin ligase complex, initiates most inherited and sporadic clear-cell renal cell carcinomas (ccRCC). Genetic inactivation of the TP53 gene in ccRCC is rare, suggesting that an alternate mechanism alleviates the selective pressure for TP53 mutations in ccRCC. Here we use a zebrafish model to describe the functional consequences of pVHL loss on the p53/Mdm2 pathway. We show that p53 is stabilized in the absence of pVHL and becomes hyperstabilized upon DNA damage, which we propose is because of a novel in vivo interaction revealed between human pVHL and a negative regulator of Mdm2, the programmed cell death 5 (PDCD5) protein. PDCD5 is normally localized at the plasma membrane and in the cytoplasm. However, upon hypoxia or loss of pVHL, PDCD5 relocalizes to the nucleus, an event that is coupled to the degradation of Mdm2. Despite the subsequent hyperstabilization and normal transcriptional activity of p53, we find that zebrafish vhl(-/-) cells are still as highly resistant to DNA damage-induced cell cycle arrest and apoptosis as human ccRCC cells. We suggest this is because of a marked increase in expression of birc5a, the zebrafish homolog of Survivin. Accordingly, when we knock down Survivin in human ccRCC cells we are able to restore caspase activity in response to DNA damage. Taken together, our study describes a new mechanism for p53 stabilization through PDCD5 upon hypoxia or pVHL loss, and reveals new clinical potential for the treatment of pathobiological disorders linked to hypoxic stress.

Xu F, Wu K, Zhao M, et al.
Expression and clinical significance of the programmed cell death 5 gene and protein in laryngeal squamous cell carcinoma.
J Int Med Res. 2013; 41(6):1838-47 [PubMed] Related Publications
OBJECTIVE: To determine the expression of the gene programmed cell death 5 (PDCD5) and its protein PDCD5 in laryngeal squamous cell carcinoma and to analyse possible correlations with clinicopathological parameters.
METHODS: PDCD5 mRNA expression was assessed using reverse transcription-polymerase chain reaction and expression of PDCD5 protein was studied using Western blot analysis and immunohistochemistry in laryngeal squamous cell carcinoma and morphologically normal para-carcinoma tissue.
RESULTS: A total of 41 laryngeal squamous cell carcinoma and 29 normal para-carcinoma tissue specimens were examined. Expression of both PDCD5 mRNA and PDCD5 protein was significantly reduced in laryngeal squamous cell carcinoma compared with normal tissue. Expression was correlated with clinical stage and histological grade, but was not associated with age, sex, location of primary tumour or the presence of lymph node metastases.
CONCLUSION: The expression of PDCD5 and its protein were shown to be reduced in laryngeal squamous cell carcinoma. The functional importance of PDCD5 as a regulating agent in cell apoptosis suggests that it may play a key role in tumour pathogenesis and development.

Fu DZ, Cheng Y, He H, et al.
The fate of Krüppel-like factor 9-positive hepatic carcinoma cells may be determined by the programmed cell death protein 5.
Int J Oncol. 2014; 44(1):153-60 [PubMed] Related Publications
Liver cancer in men is the fifth most frequently diagnosed cancer worldwide. Human Krüppel-like factor (KLF9) gene, localized on human chromosome 9q13, has been implicated in mediating a diverse range of biological processes including stem cell maintenance and differentiation of T- and B-lymphocytes. In this study, we confirmed that the levels of KLF9 mRNA and protein were lower in hepatocellular carcinoma (HCC) tissue compared to normal tissue. In addition, we confirmed that upregulation of KLF9 inhibited cell proliferation and mobility and induce apoptosis in HepG2 cells depending on programmed cell death protein 5 (PDCD5) expression. However, no interaction was found between KLF9 and PDCD5 using fluorescence resonance energy transfer (FRET) and co-immunoprecipitation (co-IP). We confirmed that PDCD5 overexpression stimulated the promoter activities of KLF9 by luciferase reporter assays.

Fu DZ, Cheng Y, He H, et al.
PDCD5 expression predicts a favorable outcome in patients with hepatocellular carcinoma.
Int J Oncol. 2013; 43(3):821-30 [PubMed] Related Publications
Liver cancer in men is the fifth most frequently diagnosed cancer worldwide. Programmed cell death 5 (PDCD5) is an apoptosis related gene and plays an important role in the pathogenesis and development of cancer. In this study, we confirmed that the levels of PDCD5 mRNA and protein were lower in hepatocellular carcinoma (HCC) tissue compared to normal tissue. PDCD5 expression was significantly associated with HBV infection, tumor number, lymph node metastasis and the survival time of the patients with HCC. In addition, the serum levels of PDCD5 and AFP in the patients were significantly positively correlated. We also confirmed that upregulation of PDCD5 was able to inhibit cell proliferation and mobility, induce apoptosis and G1 arrest. Interestingly, PDCD5 also inhibited proteasome activity similarly to the proteosome inhibitor MG132. PDCD5 could be considered as a reliable marker of favorable prognosis of HCC patients.

Hofer D, Schwach G, Ghaffari Tabrizi-Wizsy N, et al.
Christia vespertilionis plant extracts as novel antiproliferative agent against human neuroendocrine tumor cells.
Oncol Rep. 2013; 29(6):2219-26 [PubMed] Related Publications
Neuroendocrine tumors respond poorly to radiation and conventional chemotherapy, hence surgical removal of the neoplastic tissue is still the most effective way of treatment. In an attempt to find new therapeutic plant extracts of Christia vespertilionis (CV) their antitumor potential in human medullary thyroid carcinoma (MTC) and human small intestinal neuroendocrine tumor (SI-NET) cell lines were tested. Proliferation and viability were analyzed using cell counting and WST-1 assay. Apoptosis was determined by microscopy, luminescence assays for caspases 3/7, and expression studies of apoptosis-related genes. CV extracts showed antiproliferative and proapoptotic effects in all MTC and SI-NET cell lines, whereby high growth inhibition was observed by treatment with the ethylacetate-extracts (CV-45) in tumor cell lines but not in normal human fibroblasts. Furthermore CV-45 treatment resulted in alterations of gene expression of PDCD5, MTDH and TNFRSF10b in MTC as well as in SI-NET cells. The results indicate that Christia vespertilionis could serve as an anticancer therapeutic for treatment of neuroendocrine tumors.

Gao F, Ding L, Zhao M, et al.
The clinical significance of reduced programmed cell death 5 expression in human gastrointestinal stromal tumors.
Oncol Rep. 2012; 28(6):2195-9 [PubMed] Related Publications
Programmed cell death 5 (PDCD5) is a novel apoptosis-related gene with potent antitumor effects which can interact with the histone acetyltransferase Tip60 and induce DNA damage-induced apoptosis. Reduced PDCD5 expression has been found in a few types of human tumors and is also associated with the progression and prognosis of the tumors. However, the expression status and clinical significance of PDCD5 in gastrointestinal stromal tumors has not yet been analyzed. In our study, we examined PDCD5 expression in 63 tumor samples of gastrointestinal stroma at both mRNA and protein levels by RT-PCR, western blotting and immunohistochemistry. We found that 57% (16/28) of the tumor samples had a decreased PDCD5 expression at the mRNA level and 53% (35/66) of the samples were found to have decreased PDCD5 expression at the protein level, whereas PDCD5 was highly expressed in all adjacent normal gastrointestinal tissues at the mRNA or protein level. Moreover, decreased PDCD5 expression was significantly associated with clinicopathological characteristics including tumor size and mitosis. Our results suggest that PDCD5 expression plays a significant role in the malignant progression of human gastrointestinal stromal tumors and may be a key inhibitory factor.

Li H, Zhang X, Song X, et al.
PDCD5 promotes cisplatin-induced apoptosis of glioma cells via activating mitochondrial apoptotic pathway.
Cancer Biol Ther. 2012; 13(9):822-30 [PubMed] Related Publications
Glioma is one of the most common primary brain tumors. Despite surgical resection, radiotherapy, and chemotherapy, the prognosis of patients with malignant glioma remains poor. Programmed cell death 5 (PDCD5) is a newly described pro-apoptotic protein. Our previous study showed that PDCD5 downregulation in gliomas was associated with higher pathological grade. Here, we investigated the effect of PDCD5 on chemosensitivity of glioma cells and its mechanism. We demonstrated that overexpression or knockdown of PDCD5 had no significant effect on the proliferation of glioma cell lines (U87, U251, and T98G) in the absence of chemotherapeutic agents. However, PDCD5 overexpression effectively sensitized U87 cells to chemotherapeutic drugs (cisplatin, carboplatin, and vincristine) in a concentration-dependent manner, while its knockdown resulted in decreased chemosensitivity in U251, T98G, and U87 cells. Importantly, expression of PDCD5 also markedly inhibited tumor cell proliferation and colony formation in the presence of low doses of cisplatin. Furthermore, we found that PDCD5 expression promoted cisplatin-induced apoptosis, increased markedly the activation of caspase-3 and caspase-9, and decreased significantly the ratio of Bcl-2/Bax proteins, but had no effect on the activation of caspase-8. Taken together, our findings indicate that PDCD5 promotes chemosensitivity by activating mitochondria-related apoptotic pathway, and that the combination of PDCD5 and chemotherapeutic drugs such as cisplatin, is expected to be an effective therapeutic strategy for the malignant glioma.

Han XR, Sun Y, Bai XZ
The anti-tumor role and mechanism of integrated and truncated PDCD5 proteins in osteosarcoma cells.
Cell Signal. 2012; 24(8):1713-21 [PubMed] Related Publications
Osteosarcoma (OS) is a high-grade malignant bone tumor. In these studies, the cell apoptosis-related gene, programmed cell death 5 gene (PDCD5), and various fragments of it, were overexpressed in the OS cell line, MG-63. The effects of PDCD5 on MG-63 cells both in vivo and in vitro were then identified. Our results indicate that PDCD5 can induce apoptosis and G(2) phase arrest in MG-63 cells. Moreover, expression of PDCD5 in established xenografted tumors was associated with a decrease in tumor size and weight. Accordingly, the survival rate of these mice was significantly higher than that of mice bearing tumors that did not express PDCD5. To analyze the signaling pathway involved, western blotting was performed. In these assays, PDCD5 was found to inhibit the Ras/Raf/MEK/ERK signaling pathway, leading to inhibition of cyclin B and CDK1. In addition, down-regulation of ERK resulted in activation of caspase 3 and caspase 9. These results are consistent with the G(2) phase arrest observed with overexpression of PDCD5. However, a G(1) phase arrest was not observed. Therefore, proteins associated with the G(1) phase of the cell cycle were overexpressed in combination with PDCD5 overexpression. Overall, these studies demonstrate the anti-tumor activity of PDCD5 in the OS cell line, MG-63, and provide insight into relevant mechanisms that may lead to novel treatments for OS.

Xu HY, Chen ZW, Pan YM, et al.
Transfection of PDCD5 effect on the biological behavior of tumor cells and sensitized gastric cancer cells to cisplatin-induced apoptosis.
Dig Dis Sci. 2012; 57(7):1847-56 [PubMed] Related Publications
BACKGROUND: Programmed cell death 5 (PDCD5) expression is reduced in various human tumor cells, and the protein concentration and nuclear translocation of PDCD5 is also observed during tumor cell apoptosis.
AIMS: The purpose of this study was to investigate the differential expression of PDCD5 in six gastric cell lines, and to explore the changes of biological behavior mechanism underlying enhanced apoptosis-inducing effects of cisplatin by PDCD5 over-expression on gastric cancer BGC823 cells.
METHODS: RT-PCR and real-time PCR were used to determine PDCD5 expression. BGC823/PDCD5 cells were assessed the cellular proliferating ability by MTT assay, soft agar cloning experiments and tumorigenicity in nude mice experiments in vivo. The effects of cisplatin in combination with PDCD5 on the proliferation and apoptosis were measured by MTT, Annexin-V-FITC/PI dual labeling and cell cycle analysis, respectively. Immunofluorescence was used to detect co-localization of p53 and PDCD5 protein to explore the mechanism underlying the synergistic therapeutic effect of PDCD5 with cisplatin (5 μg/ml for 24 h).
RESULTS: PDCD5 had the highest expression level in the GES1 cell among other cell lines. The growths of BGC823 cells transfected with PDCD5 for six (6th) or 17 (17th) days were both slower than that of BGC823 and BGC823/Neo (P < 0.01). The stable transfection of PDCD5 demonstrated G2/M cell cycle arrest, increased apoptosis and nuclear translocation of PDCD5 and p53 after cisplatin treatment.
CONCLUSIONS: Stable transfection of the PDCD5 gene can inhibit the growth of the BGC823 cell line and notably improve apoptosis-inducing effects of cisplatin, indicating a novel strategy for better chemotherapeutic effects on gastric cancer.

Zhang X, Wang X, Song X, et al.
Clinical and prognostic significance of lost or decreased PDCD5 expression in human epithelial ovarian carcinomas.
Oncol Rep. 2011; 25(2):353-8 [PubMed] Related Publications
Programmed cell death 5 (PDCD5) is a novel apoptosis-promoting protein. Although the decreased expression of PDCD5 has been recently found in a few types of human tumors, the status and significance of PDCD5 in ovarian cancer has not been evaluated. In the present study, we detected PDCD5 expression in 20 normal human ovaries and 26 serous cystadenomas and 41 serous cystadenocarcinomas by RT-PCR, Western blotting and immunohistochemistry, and analyzed the relationship between PDCD5 expression and clinicopathological data or patient survival. PDCD5 was expressed in all normal ovaries and serous cystadenomas, 80% (16/20) of normal ovarian tissues and 76.9% (20/26) of serous cystadenomas with moderate or strong PDCD5 protein expression. In contrast, 22% (9/41) of serous cystadenocarcinomas had no detectable PDCD5 protein expression and 46.3% (19/41) exhibited weak PDCD5 expression. The overall expression of PDCD5 in serous cystadenocarcinoma was significantly lower compared with normal ovarian tissues or serous cystadenomas (p<0.01). Furthermore, lost or decreased PDCD5 expression in serous cystadenocarcinomas was associated significantly with FIGO stage (p<0.05) and poorer disease-specific survival of patients (p<0.05). In conclusion, our data suggest that lost or reduced PDCD5 expression may contribute to the pathogenesis of human serous cystadenocarcinomas.

Chen C, Zhou H, Xu L, et al.
Prognostic significance of downregulated expression of programmed cell death 5 in chondrosarcoma.
J Surg Oncol. 2010; 102(7):838-43 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Programmed Cell Death 5 (PDCD5) is a novel apoptosis-related gene and deregulation of PDCD5 is involved in tumorigenicity. This study was designed to investigate the expression level of PDCD5 and to clarify its clinical significance in chondrosarcoma.
METHODS: The mRNA and protein levels of PDCD5 in chondrosarcoma and matched corresponding non-tumor tissues were evaluated by real-time PCR and Western blot, respectively. The expression of PDCD5 protein was investigated by immunohistochemistry assays in chondrosarcoma, and its association with clinicopathologic factors and overall survival was also analyzed.
RESULTS: The mRNA and protein levels of PDCD5 were significantly decreased in chondrosarcoma compared with corresponding non-tumor tissues. Low expression of PDCD5 protein was 61.8% (21/34) in chondrosarcomas, as compared 12.5% (1/8) in normal bones, as well as compared 23.5% (4/17) in benign cartilage tumors. PDCD5 expression was correlated with anatomical location and histological grade. The survival rate of patients with low-PDCD5 tumors was lower than that of patients with high-PDCD5 tumors. Multivariate analysis revealed that the downregulated expression of PDCD5 was an independent prognostic factor for overall survival.
CONCLUSIONS: PDCD5 is downregulated in chondrosarcoma and might be an independent prognostic factor for overall survival of chondrosarcoma patients.

Yin A, Jiang Y, Zhang X, et al.
Transfection of PDCD5 sensitizes colorectal cancer cells to cisplatin-induced apoptosis in vitro and in vivo.
Eur J Pharmacol. 2010; 649(1-3):120-6 [PubMed] Related Publications
This study was purposed to explore the mechanism of augmenting apoptosis-inducing effects of cisplatin on colorectal cancer SW480 cells by stable transfection of Programmed Cell Death 5 (PDCD5) gene, both in vitro and in vivo. The expression level of PDCD5 of SW480 cells stably transfected with PDCD5 (SW480/PDCD5) and pcDNA3.1/Neo(+) empty vector stably transfected cells (SW480/Neo) was examined by real-Time RT-PCR and Western blot. The effects of cisplatin in combination with PDCD5 on the proliferation and apoptosis of colorectal cancer cells were measured by using MTT analysis, Hoechst 33258 analysis and flow cytometry with Annexin-V-FITC/PI dual labeling, respectively. To examine the combination therapeutic effect of PDCD5 and cisplatin, tumor xenograft model was prepared for in vivo study. The results showed that PDCD5 levels of SW480/PDCD5 were higher than SW480 and SW480/Neo, respectively. The PDCD5 enhanced the apoptotic percentage of SW480/PDCD5 cells induced by cisplatin, as compared SW480 and SW480/Neo, respectively. In in vivo study, the transfection of PDCD5 increased the efficacy of cisplatin-induced inhibition of tumor growth in nude mice. It is concluded that stable transfection of PDCD5 gene can notably improve apoptosis-inducing effects of cisplatin on colorectal cancer cells, which is a novel strategy to better chemotherapeutic effects on colorectal cancer.

Du YJ, Xiong L, Lou Y, et al.
Reduced expression of programmed cell death 5 protein in tissue of human prostate cancer.
Chin Med Sci J. 2009; 24(4):241-5 [PubMed] Related Publications
OBJECTIVE: To investigate the expression of programmed cell death 5 (PDCD5) in tissues of normal human prostate (NP), benign prostatic hyperplasia (BPH), and prostate cancer (PCa) in order to assess the clinical role of PDCD5 in PCa.
METHODS: PDCD5 expression was determined by EnVision immunohistochemical staining in formalin-fixed and paraffin-embedded specimens obtained from 12 subjects with NP, 22 with BPH, and 22 with PCa. In addition, PCa cases were classified as low/middle-risk (Gleason sum < or = 7) and high-risk (Gleason sum >7) on the basis of Gleason grade. Positive expression rates and intensity of PDCD5 protein were observed under light microscope and analyzed with computer imaging technique. Expression of PDCD5 was compared among different prostatic tissues.
RESULTS: The expression of PDCD5 was significantly lower in tissue of PCa than in tissues of NP and BPH (P<0.01). However, there was no significant difference in PDCD5 expression between tissues of NP and BPH. In addition, the expression of PDCD5 was further downregulated with the increase of Gleason sum in PCa.
CONCLUSIONS: By downregulating apoptosis, low PDCD5 expression may play an important role in the occurrence and development of PCa. PDCD5 is supposed to have a potential clinical value to be a new predictor of progression and target of gene therapy in PCa.

Xie M, Niu JH, Chang Y, et al.
A novel triple-regulated oncolytic adenovirus carrying PDCD5 gene exerts potent antitumor efficacy on common human leukemic cell lines.
Apoptosis. 2009; 14(9):1086-94 [PubMed] Related Publications
PDCD5 (programmed cell death 5) accelerates apoptosis of certain tumor cells and the replication-defective Ad-PDCD5 may be a promising agent for enhancing chemosensitivity. In this study, a triple-regulated conditionally replicating adenoviruses (CRAd) carrying PDCD5 gene expression cassette, SG611-PDCD5, was engineered. In SG611-PDCD5, the E1a gene with a deletion of 24 nucleotides within CR2 region is controlled under the human telomerase reverse transcriptase (hTERT) promoter, the E1b gene expression is directed by the hypoxia response element (HRE), whereas the PDCD5 gene is controlled by the cytomegalovirus promoter. The tumor-selective replication of this virus and its antitumor efficacy were characterized in several leukemic cell lines in vitro and in xenograft models of human leukemic cell line in nude mice. It was found by RQ-RT-PCR assay that SG611-PDCD5 expressed PDCD5 efficiently in leukemic cells. In K562 tumor xenograft models, SG611-PDCD5 displayed a tumor killing capacity. At a dose of 1 x 10(9) plaque-forming units, SG611-PDCD5 alone could completely inhibit the tumor growth and more effective than replication-defective Ad-PDCD5. Histopathologic examination revealed that SG611-PDCD5 administration resulted in leukemic cell apoptosis. We concluded that the triple-regulated SG611-PDCD5, as a more potent and safer antitumor therapeutic, could provide a new strategy for leukemia biotherapy.

Su DM, Zhang Q, Wang X, et al.
Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy.
Mol Cancer Ther. 2009; 8(5):1292-304 [PubMed] Free Access to Full Article Related Publications
Human malignant melanoma has poor prognosis because of resistance to apoptosis and therapy. We describe identification of the expression profile of 1,037 mitochondria-focused genes and 84 survival-apoptosis genes in 21 malignant melanoma cell lines and 3 normal melanocyte controls using recently developed hMitChip3 cDNA microarrays. Unsupervised hierarchical clustering analysis of 1,037 informative genes, and 84 survival-apoptosis genes, classified these malignant melanoma cell lines into type A (n = 12) and type B (n = 9). Three hundred fifty-five of 1,037 (34.2%) genes displayed significant (P ≤ 0.030; false discovery rate ≤ 3.68%) differences (± ≥ 2.0-fold) in average expression, with 197 genes higher and 158 genes lower in type A than in type B. Of 84 genes with known survival-apoptosis functions, 38 (45.2%) displayed the significant (P < 0.001; false discovery rate < 0.15%) difference. Antiapoptotic (BCL2, BCL2A1, PPARD, and RAF1), antioxidant (MT3, PRDX5, PRDX3, GPX4, GLRX2, and GSR), and proapoptotic (BAD, BNIP1, APAF1, BNIP3L, CASP7, CYCS, CASP1, and VDAC1) genes expressed at higher levels in type A than in type B, whereas the different set of antiapoptotic (PSEN1, PPP2CA, API5, PPP2R1B, PPP2R1A, and FIS1), antioxidant (HSPD1, GSS, SOD1, ATOX1, and CAT), and proapoptotic (ENDOG, BAK1, CASP2, CASP4, PDCD5, HTRA2, SEPT4, TNFSF10, and PRODH) genes expressed at lower levels in type A than in type B. Microarray data were validated by quantitative reverse transcription-PCR. These results showed the presence of two types of malignant melanoma, each with a specific set of dysregulated survival-apoptosis genes, which may prove useful for development of new molecular targets for therapeutic intervention and novel diagnostic biomarkers for treatment and prognosis of malignant melanoma.

Tsuzuki S, Karnan S, Horibe K, et al.
Genetic abnormalities involved in t(12;21) TEL-AML1 acute lymphoblastic leukemia: analysis by means of array-based comparative genomic hybridization.
Cancer Sci. 2007; 98(5):698-706 [PubMed] Related Publications
The TEL (ETV6)-AML1 (RUNX1) chimeric gene fusion is the most common genetic abnormality in childhood acute lymphoblastic leukemias. Evidence suggests that this chimeric gene fusion constitutes an initiating mutation that is necessary but insufficient for the development of leukemia. In a search for additional genetic events that could be linked to the development of leukemia, we applied a genome-wide array-comparative genomic hybridization technique to 24 TEL-AML1 leukemia samples and two cell lines. It was found that at least two chromosomal imbalances were involved in all samples. Recurrent regions of chromosomal imbalance (>10% of cases) and representative involved genes were gain of chromosomes 10 (17%) and 21q (25%; RUNX1) and loss of 12p13.2 (87%; TEL), 9p21.3 (29%; p16INK4a/ARF), 9p13.2 (25%; PAX5), 12q21.3 (25%; BTG1), 3p21 (21%; LIMD1), 6q21 (17%; AIM1 and BLIMP1), 4q31.23 (17%; NR3C2), 11q22-q23 (13%; ATM) and 19q13.11-q13.12 (13%; PDCD5). Enforced expression of TEL and to a lesser extent BTG1, both single genes known to be located in their respective minimum common region of loss, inhibited proliferation of the TEL-AML1 cell line Reh. Together, these findings suggest that some of the genes identified as lost by array-comparative genomic hybridization may partly account for the development of leukemia.

Spinola M, Meyer P, Kammerer S, et al.
Association of the PDCD5 locus with lung cancer risk and prognosis in smokers.
J Clin Oncol. 2006; 24(11):1672-8 [PubMed] Related Publications
PURPOSE: Whole-genome scan association analysis was carried out to identify genetic variants predictive of lung cancer risk in smokers and to confirm the identified variants in an independent sample.
PATIENTS AND METHODS: A case-control study was performed using two pools consisting of DNA from 322 German smoking lung cancer patients and 273 healthy smoking controls, respectively. A replication study was carried out using 254 Italian lung adenocarcinoma (ADCA) patients and 235 healthy controls.
RESULTS: Patients with genotypes GG or CG for the rs1862214 single nucleotide polymorphism, 5' upstream of the programmed cell death 5 (PDCD5) gene, compared with those with the common genotype CC showed an increased risk of lung cancer (odds ratio, 1.6; 95% CI, 1.2 to 2.1) and a higher incidence of poor clinical stage disease (hazard ratio [HR], 1.9; 95% CI, 1.1 to 3.4; P = .023), nodal involvement (HR, 1.9; 95% CI, 1.1 to 3.6; P = .033), and short-term survivorship (HR, 1.8; 95% CI, 1.2 to 2.6, P = .003). PDCD5 mRNA expression levels were approximately 2.4-fold lower in lung ADCA as compared to normal lung tissue. Human NCI-H520 cancer cells transfected with PDCD5 cDNA showed decreased colony-forming ability.
CONCLUSION: These results suggest that the rs1862214 polymorphism in PDCD5 is predictive for lung cancer risk and prognosis, and that PDCD5 may represent a novel tumor suppressor gene influencing lung cancer.

Yang YH, Zhao M, Li WM, et al.
Expression of programmed cell death 5 gene involves in regulation of apoptosis in gastric tumor cells.
Apoptosis. 2006; 11(6):993-1001 [PubMed] Related Publications
The protein of programmed cell death 5 (PDCD5) is believed to participate in regulation of apoptosis. Although PDCD5 is reducibly expressed in various human tumors, it is not clear which expression level of PDCD5 is in gastric cancer (GC). In this study, we have systematically employed the approaches of RT-PCR, Real- time PCR, Immunohistochemistry (IHC), Immunofluorescence staining (IFS) and Western blot to determine the PDCD5 expression in GC cells and primary tumors, at mRNA and protein level, respectively. Our data revealed that the positive rate of PDCD5 expression in the gastric tumor tissues was significantly less than that of the normal tissues (14 out of 102 vs 36 out of 51), whereas, the decreased expression of PDCD5 protein was well correlated with the up-regulated expression of Bcl-2 in these tissues, and the up-regulated expression and nuclear translocation of PDCD5 protein were verified in the apoptotic GC cells induced by Diallyl trisulfide (DATS). Furthermore, the survival curve has suggested that the more PDCD5 expressions were found in the patients, the longer the survival periods were. Therefore, our observations lay down a reasonable postulation that PDCD5 may play a key role to regulate the apoptotic processes in the GC cells and gastric tumors.

Ruan GR, Qin YZ, Chen SS, et al.
Abnormal expression of the programmed cell death 5 gene in acute and chronic myeloid leukemia.
Leuk Res. 2006; 30(9):1159-65 [PubMed] Related Publications
To clarify whether expression of the programmed cell death 5 (PDCD5) gene in leukemic cells is abnormal, real-time quantitative reverse transcription polymerase chain reaction (RQ-RT-PCR) was used to examine its expression in marrow cells from leukemia patients. We found lower PDCD5 in both AML and CML marrow cells than in normal donor marrow cells. A negative correlation was found between relative levels of PDCD5 and BCR/ABL expression in all CML patients and in CML patients in the advanced phase. Treatment with the ABL tyrosine kinase inhibitor Imatinib mesylate increased PDCD5 expression in K562 and MEG-01 cells. These findings suggest that abnormal expression of PDCD5 in leukemia may be involved in the pathomechanism of AML and CML.

Ma X, Ruan G, Wang Y, et al.
Two single-nucleotide polymorphisms with linkage disequilibrium in the human programmed cell death 5 gene 5' regulatory region affect promoter activity and the susceptibility of chronic myelogenous leukemia in Chinese population.
Clin Cancer Res. 2005; 11(24 Pt 1):8592-9 [PubMed] Related Publications
PURPOSE: Chronic myelogenous leukemia (CML) is a disease characterized cytogenetically by the presence of the Philadelphia chromosome. Recent studies suggested that altered PDCD5 expression may have significant implications in CML progression. The aim of this study was to identify single-nucleotide polymorphisms (SNP) within the programmed cell death 5 (PDCD5) promoter region and show their functional relevance to PDCD5 expression as well as their genetic susceptibility to CML.
EXPERIMENTAL DESIGN: One hundred twenty-nine CML subjects and 211 healthy controls were recruited for identification of SNPs and subsequent genetic analysis. Luciferase reporter assays were carried out to show the functional significance of the SNPs located in the promoter region to PDCD5 expression. Real-time quantitative PCR and Western blot analysis were done to determine the expression differences of PDCD5 in CML patients with different genotypes.
RESULTS: Two SNPs were identified within the PDCD5 promoter. They are -27A>G and -11G>A (transcription start site as position 1), respectively. The complete linkage disequilibrium was found between these two polymorphisms. The frequencies of -27G+/-11A+ genotype and -27G/-11A allele were significantly higher in CML patients than in healthy controls (genotype: 26.36% versus 11.85%, chi2=11.75, P<0.01; allele: 13.57% versus 6.40%, chi2=9.48, P<0.01). Luciferase reporter assays revealed that the promoter with -27G/-11A had significantly lower transcriptional activity and could not be up-regulated after apoptotic stimulations compared with the promoter with -27A/-11G. PDCD5 expression analysis in mononuclear cells derived from CML patients and cell lines with different -27/-11 genotypes showed consistent results with the reporter assays.
CONCLUSIONS: These data suggest that -27G/-11A is associated with reduced PDCD5 promoter activity and increased susceptibility to CML.

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