Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-Troglitazone-induced Apoptosis in Prostate Cancer Cells Involve AMP-activated Protein Kinase

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 thiazolidined...

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Bibliographic Details
Published in:The Journal of biological chemistry 2015-09, Vol.290 (36), p.21865-21875
Main Authors: Santha, Sreevidya, Viswakarma, Navin, Das, Subhasis, Rana, Ajay, Rana, Basabi
Format: Article
Language:English
Subjects:
AMP-activated kinase (AMPK)
AMP-Activated Protein Kinases - genetics
AMP-Activated Protein Kinases - metabolism
apoptosis
Apoptosis - drug effects
beta Catenin - metabolism
beta-catenin (B-catenin)
Blotting, Western
Cell Biology
Cell Line, Tumor
Cell Survival - drug effects
Cell Survival - genetics
Chromans - pharmacology
Dose-Response Relationship, Drug
Drug Synergism
Humans
Male
PPAR gamma - agonists
PPAR gamma - genetics
PPAR gamma - metabolism
prostate cancer
Prostatic Neoplasms - enzymology
Prostatic Neoplasms - genetics
Prostatic Neoplasms - pathology
RNA Interference
Signal Transduction - drug effects
Signal Transduction - genetics
Thiazolidinediones - pharmacology
Time Factors
TNF-Related Apoptosis-Inducing Ligand - pharmacology
TRAIL
Troglitazone
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Summary: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 pACCS79 (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. Background: Combination of TRAIL with PPARγ ligands has been shown to ameliorate TRAIL resistance, but the mechanism involved is still unknown. Results: Inhibition of AMPK activity antagonizes TRAIL and troglitazone combination-induced apoptosis and attenuates caspase cleavage in prostate cancer cells. Conclusion: AMPK is involved in mediating TRAIL-troglitazone-induced apoptosis. Significance: Targeting AMPK by TRAIL and troglitazone combination might be an effective means of sensitizing apoptosis-resistant prostate cancer cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M115.663526