title: Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-Troglitazone-induced Apoptosis in Prostate Cancer Cells Involve AMP-activated Protein Kinase.
abstract: Prostate cancer (PCa) is one of the most frequently diagnosed cancers in men with limited treatment options for the hormone-resistant forms. Development of novel therapeutic options is critically needed to target advanced forms. Here we demonstrate that combinatorial treatment with the thiazolidinedione troglitazone (TZD) and TNF-related apoptosis-inducing ligand (TRAIL) can induce significant apoptosis in various PCa cells independent of androgen receptor status. Because TZD is known to activate AMP-activated protein kinase (AMPK), we determined whether AMPK is a molecular target mediating this apoptotic cascade by utilizing PCa cell lines stably overexpressing AMPKα1 dominant negative (C4-2-DN) or empty vector (C4-2-EV). Our results indicated a significantly higher degree of apoptosis with TRAIL-TZD combination in C4-2-EV cells compared with C4-2-DN cells. Similarly, results from a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed a larger reduction of viability of C4-2-EV cells compared with C4-2-DN cells when treated with TRAIL-TZD, thus suggesting that C4-2-DN cells were more apoptosis-resistant. Additionally, siRNA-mediated knockdown of endogenous AMPKα1 expression showed a reduction of TRAIL-TZD-induced apoptosis, further confirming the participation of AMPK in mediating this apoptosis. Apoptosis induction by this combinatorial treatment was also associated with a cleavage of β-catenin that was inhibited in both C4-2-DN cells and those cells in which AMPKα1 was knocked down. In addition, time course studies showed an increase in pACC(S79) (AMPK target) levels coinciding with the time of apoptosis. These studies indicate the involvement of AMPK in TRAIL-TZD-mediated apoptosis and β-catenin cleavage and suggest the possibility of utilizing AMPK as a therapeutic target in apoptosis-resistant prostate cancer.
authors.affiliation: From the Department of Medicine, Division of Gastroenterology & Nutrition and.
authors.forename: Sreevidya
authors.initials: S
authors.lastname: Santha
authors.affiliation: the Department of Molecular Pharmacology & Therapeutics, Loyola University Chicago, Maywood, Illinois 60153 and.
authors.forename: Navin
authors.initials: N
authors.lastname: Viswakarma
authors.affiliation: the Department of Molecular Pharmacology & Therapeutics, Loyola University Chicago, Maywood, Illinois 60153 and.
authors.forename: Subhasis
authors.initials: S
authors.lastname: Das
authors.affiliation: the Department of Molecular Pharmacology & Therapeutics, Loyola University Chicago, Maywood, Illinois 60153 and the Hines VA Medical Center, Hines, Illinois 60141.
authors.forename: Ajay
authors.initials: A
authors.lastname: Rana
authors.affiliation: From the Department of Medicine, Division of Gastroenterology & Nutrition and the Hines VA Medical Center, Hines, Illinois 60141 arnavr_299@hotmail.com.
authors.forename: Basabi
authors.initials: B
authors.lastname: Rana
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D000077288:Troglitazone; D051176:beta Catenin / Q000378:metabolism
chemical_list: D002839:Chromans; D047495:PPAR gamma; D053221:TNF-Related Apoptosis-Inducing Ligand; D045162:Thiazolidinediones; D051176:beta Catenin; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D000077288:Troglitazone
keywords: AMP-activated kinase (AMPK); TRAIL; apoptosis; beta-catenin (B-catenin); prostate cancer