Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARgamma.
Certain members of the thiazolidenedione family of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, such as troglitazone and ciglitazone, exhibit antitumor effects; however, the underlying mechanism remains inconclusive. This study shows that the effect of these thiazolidenedione members on apoptosis in prostate cancer cells is independent of PPARgamma activation. First, close structural analogues of thiazolidenediones, whereas devoid of PPARgamma activity, retain the ability to induce apoptosis with equal potency. Second, both PC-3 (PPARgamma-expressing) and LNCaP (PPARgamma-deficient) cells are sensitive to apoptosis induction by troglitazone and its PPARgamma-inactive analogue irrespective of their PPARgamma expression status. Third, rosiglitazone and pioglitazone, potent PPARgamma agonists, show marginal effects on apoptosis even at high concentrations. Evidence indicates that the apoptotic effect of troglitazone, ciglitazone, and their PPARgamma-inactive analogues 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethoxy)-benzylidene]-2,4-thiazolidine-dione (Delta2-TG) and 5-[4-(1-methyl-cyclohexylmethoxy)-benzylidene]-thiazolidine-2,4-dione, respectively, is in part attributable to their ability to inhibit the anti-apoptotic functions of Bcl-xL and Bcl-2. Treatment of PC-3 cells with troglitazone or Delta2-TG led to reduced association of Bcl-2 and Bcl-xL with Bak, leading to caspase-dependent apoptosis. Bcl-xL overexpression protects LNCaP cells from apoptosis induction by troglitazone and Delta2-TG in an expression level-dependent manner. Considering the pivotal role of Bcl-xL/Bcl-2 in regulating mitochondrial integrity, this new mode of mechanism provides a framework to account for the PPARgamma-independent action of thiazolidenediones in inducing apoptosis in cancer cells. Moreover, dissociation of these two pharmacologic activities provides a molecular basis to develop novel Bcl-xL/Bcl-2 inhibitors, of which the proof of principle is illustrated by a Delta2-TG analogue with potent in vivo antitumor activities.
Shiau
Chung-Wai
CW
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, Ohio, USA.
Yang
Chih-Cheng
CC
Kulp
Samuel K
SK
Chen
Kuen-Feng
KF
Chen
Chang-Shi
CS
Huang
Jui-Wen
JW
Chen
Ching-Shih
CS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; C494773:Bak1 protein, mouse; C494812:Bcl2l1 protein, mouse; D002839:Chromans; D008565:Membrane Proteins; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D045162:Thiazolidinediones; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D000077288:Troglitazone