Beyond Peroxisome Proliferator-Activated Receptor Gamma Signaling: The Multi-Facets of the Antitumor Effect of Thiazolidinediones

Abstract

Certain members of the thiazolidinedione (TZD) family of the peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, such as troglitazone and ciglitazone, exhibit antitumor activities; however, the underlying mechanism remains inconclusive. Substantial evidence suggests that the antiproliferative effect of these TZD members in cancer cells is independent of PPAR gamma activation. To discern the role of PPAR gamma in the antitumor effects of TZDs, we have synthesized PPAR gamma- inactive TZD analogs which, although devoid of PPAR gamma activity, retain the ability to induce apoptosis with a potency equal to that of their parental TZDs in cancer cell lines with varying PPAR gamma expression status. Mechanistic studies from this and other laboratories have further suggested that troglitazone and ciglitazone mediate antiproliferative effects through a complexity of PPAR gamma -independent mechanisms. Evidence indicates that troglitazone and ciglitazone block BH3 domain- mediated interactions between the anti apoptotic Bcl-2 (B-cell leukemia/ lymphoma 2) members Bcl-2/Bcl-xL and proapoptotic Bcl-2 members. Moreover, these TZDs facilitate the degradation of cyclin D1 and caspase-8-related FADD-like IL- 1-converting enzyme (FLICE)-inhibitory protein through proteasome-mediated proteolysis, and down-regulate the gene expression of prostate-specific antigen gene expression by inhibiting androgen activation of the androgen response elements in the promoter region. More importantly, dissociation of the effects of TZDs on apoptosis from their original pharmacological activity (i.e. PPAR gamma activation) provides a molecular basis for the exploitation of these compounds to develop different types of molecularly targeted anticancer agents. These TZD- derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment.