Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARγ

Chung Wai Shiau, Chih Cheng Yang, Samuel K. Kulp, Kuen Feng Chen, Chang Shi Chen, Jui Wen Huang, Ching Shih Chen

Research output: Contribution to journalArticlepeer-review

188 Citations (Scopus)

Abstract

Certain members of the thiazolidenedione family of the peroxisome proliferator-activaled receptor γ (PPARγ) 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 PPARγ activation. First, close structural analogues of thiazolidenediones, whereas devoid of PPARγ activity, retain the ability to induce apoptosis with equal potency. Second, both PC-3 (PPARγ- expressing) and LNCaP (PPARγ-deficient) cells are sensitive to apoptosis induction by troglitazone and its PPARγ-inactive analogue irrespective of their PPARγ expression status. Third, rosiglitazone and pioglitazone, potent PPARγ agonists, show marginal effects on apoptosis even at high concentrations. Evidence indicates that the apoptotic effect of troglitazone, ciglitazone, and their PPARγ-inactive analogues 5-[4-(6-hydroxy-2,5,7,8- tetramethyl-chroman-2-ylmethoxy)-benzylidene]-2,4-thiazolidine-dione (Δ2-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 Δ2-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 Δ2-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 PPARγ-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 Δ2-TG analogue with potent in vivo antitumor activities.

Original languageEnglish
Pages (from-to)1561-1569
Number of pages9
JournalCancer Research
Volume65
Issue number4
DOIs
Publication statusPublished - 2005 Feb 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARγ'. Together they form a unique fingerprint.

Cite this