Beyond peroxisome proliferator-activated receptor γ signaling: The multi-facets of the antitumor effect of thiazolidinediones
Journal
Endocrine-Related Cancer
Journal Volume
13
Journal Issue
2
Pages
401-413
Date Issued
2006
Author(s)
Abstract
Certain members of the thiazolidinedione (TZD) family of the peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ activation. To discern the role of PPARγ in the antitumor effects of TZDs, we have synthesized PPARγ-inactive TZD analogs which, although devoid of PPARγ activity, retain the ability to induce apoptosis with a potency equal to that of their parental TZDs in cancer cell lines with varying PPARy expression status. Mechanistic studies from this and other laboratories have further suggested that troglitazone and ciglitazone mediate antiproliferative effects through a complexity of PPARγ-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. PPARγ 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. ? 2006 Society for Endocrinology.
SDGs
Other Subjects
2,4 thiazolidinedione derivative; androgen; BH3 protein; caspase 8; ciglitazone; cyclin D1; FLICE inhibitory protein; peroxisome proliferator activated receptor gamma; peroxisome proliferator activated receptor gamma agonist; pioglitazone; prostate specific antigen; protein bcl 2; protein bcl xl; rosiglitazone; troglitazone; antineoplastic activity; apoptosis; breast cancer; cancer cell; cancer prevention; cell cycle regulation; cell proliferation; cell strain MCF 7; drug activity; drug binding; drug effect; drug efficacy; drug mechanism; drug potentiation; drug structure; gene control; gene expression; hormone response; human; prostate cancer; protein degradation; protein expression; protein function; protein interaction; review; signal transduction; Antineoplastic Agents; Cyclin D1; Humans; Neoplasms; PPAR gamma; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins c-bcl-2; Thiazolidinediones
Type
journal article