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Pioglitazone inhibits cancer cell growth through STAT3 inhibition and enhanced AIF expression via a PPARγ‐independent pathway
Author(s) -
Tsubaki Masanobu,
Takeda Tomoya,
Tomonari Yoshika,
Kawashima Keishi,
Itoh Tatsuki,
Imano Motohiro,
Satou Takao,
Nishida Shozo
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26225
Subject(s) - pioglitazone , peroxisome proliferator activated receptor , chemistry , stat3 , cancer research , cell growth , microbiology and biotechnology , signal transduction , biology , receptor , endocrinology , biochemistry , diabetes mellitus , type 2 diabetes
Pioglitazone is an anti‐diabetic agent that belongs to the thiazolidinedione class, which target peroxisome proliferator‐activated receptor γ (PPARγ), a transcription factor in the nuclear receptor family. Different cancer cells expressing high levels of PPARγ and PPARγ ligands induce cell cycle arrest, cell differentiation, and apoptosis. However, the mechanisms underlying these processes remain unknown. Here, we investigated the mechanism underlying pioglitazone‐induced apoptosis in human cancer cells. We showed that at similar concentrations, pioglitazone induced death in cancer cells expressing high or low levels of PPARγ. Combined treatment of pioglitazone and GW9662, a PPARγ antagonist, did not rescue this cell death phenotype. Z‐VAD‐fmk, a pan‐caspase inhibitor, did not reverse pioglitazone‐induced apoptosis in cancer cells expressing PPARγ at high or low levels. Pioglitazone suppressed the activation of signal transducers and activator of transcription 3 (STAT3) and Survivin expression, and enhanced the apoptosis‐inducing factor (AIF) levels in these cells. Furthermore, pioglitazone enhanced the cytotoxic effect of cisplatin and oxaliplatin by suppressing Survivin and increasing AIF expression. These results indicated that pioglitazone induced apoptosis via a PPARγ‐independent pathway, thus describing pioglitazone as a potential therapeutic agent for controlling the progression of different cancers.