title: PDCD6 additively cooperates with anti-cancer drugs through activation of NF-κB pathways.
abstract: The expression of programmed cell death 6 (PDCD6) is known to be down-regulated in cancer cell lines and ovarian cancer tissues compared to normal cells and tissues. In the current study, we characterized the specific function of PDCD6 as a novel pro-apoptotic protein. To define the roles of PDCD6 and cisplatin in tumorigenesis, we either over-expressed PDCD6 or treated it with cisplatin in SKOV-3 ovarian cancer cells. Both PDCD6 and cisplatin respectively inhibited cancer cell proliferation in a dose-dependent manner. The combined treatment of PDCD6 and cisplatin was more effective at suppressing cell growth than with either drug treatment alone, but had no effect with the treatment of caspase-3 and caspase-9 inhibitors. Cleavages of caspase-3, -8, -9, and poly (ADP-ribose) polymerase (PARP) in PDCD6-overexpressing cells were significantly increased after cisplatin treatment. Cell cycle analysis highly correlated with down-regulation of cyclin D1 and CDK4, and the induction of p16 and p27 as a cyclin-dependent kinase inhibitor. Additionally, PDCD6 also suppressed the phosphorylation of signaling regulators downstream of PI3K, including PDK1 and Akt. PDCD6 promotes TNFα-dependent apoptosis through the activation of NF-κB signaling pathways, increasing Bax, p53, and p21 expression, while also down-regulating Bcl-2 and Bcl-xL expression. The p21 and p53 promoter luciferase activities were enhanced by PDCD6, while there was no affect in p53(-/-) and p21(-/-). At the same time, p53 activity was confirmed by UV irradiation and siPDCD6. Taken together, these results provide evidence that PDCD6 can mediate the pro-apoptotic activity of cisplatin or TNFα through the down-regulation of NF-κB expression.
authors.affiliation: Department of Obstetrics and Gynecology, Hallym University, Seoul, Republic of Korea.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Jeong Heon
authors.initials: JH
authors.lastname: Lee
authors.forename: Gwang-Beom
authors.initials: GB
authors.lastname: Lee
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Byun
authors.forename: Boh-Ram
authors.initials: BR
authors.lastname: Kim
authors.forename: Chan-Yong
authors.initials: CY
authors.lastname: Park
authors.forename: Hong-Bae
authors.initials: HB
authors.lastname: Kim
authors.forename: Seung Bae
authors.initials: SB
authors.lastname: Rho
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019938:Cyclin D1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D002945:Cisplatin; D019938:Cyclin D1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C097753:PDCD6 protein, human; C000631429:PDK1 protein, human