Thiazolidinediones inhibit cell growth of human ovarian cancer cells via PPAR-Γ & p53- independent pathway

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Peroxisome proliferator-activated receptor gamma (PPAR-Γ) agonists, such as the antidiabetic thiazolidinedione drugs (TZDs), have recently been demonstrated to affect proliferation, differentiation, and apoptosis of different cell types. Recent in vitro and in vivo studies suggest the importance of specific PPAR-Γ ligands as cell cycle modulators for cancer treatment. To investigate the mechanism of anticancer effect of TZDs on human ovarian cancers, TZDs were tested on various human ovarian cancer cell line. The treatment of human ovarian cancer cells (NIH:OVCAR3, SKOV3, SNU8, SNU840, SNU251, 2774) with troglitazone (TGZ), a synthetic PPAR-Γ ligand, induced a dose-dependent inhibition of ovarian cancer cell growth. Also, ovarian cancer cells were treated with other PPAR-Γ ligands (pioglitazone, ciglitazone) in various concentrations and showed similar results. Various expression of PPAR-Γ mRNA was observed in human ovarian cancer cell lines by RT-PCR, but the growth inhibition was not dependent on the amount of PPAR-Γ mRNA. TZD-mediated growth inhibition was not augmented by co-treatment of 9-cis retinoic acid, a synthetic ligand of retinoic acid receptor-α. Although these compound (TGZ) bind to PPAR-Γ transcription factors as agonists, these evidence suggests that TGZ acts independently of PPAR-Γ in many functions, including apoptosis. Flow cytometry showed that the cell cycle was arrested at the G1 phase and followed by the appearance of a sub-G1 peak. TGZ increased the number of apoptotic cells in 2774, SNU 251, but not in SKOV3, SNU840, SNU8, NIH:OVCAR3 cells. DNA ladder formation was observed in 2774 and SNU251 after treatment with TGZ or ciglitazone for 24hr and 48hr. This was confirmed by the finding of increased in BAX protein on treatment with TZD by Western blotting. p53 has been implicated in the TZDs-mediated control of the cell cycle, cell differentiation, DNA repair, programmed cell death from previous reports. However, the growth inhibition does not seem to be dependent on p53 protein expression levels in ovarian cancers. This study showed that PPAR-Γ ligands were able to induce growth suppression in ovarian cancer cells via a p53-independent and PPAR-Γ independent pathway. The tumor suppressive effects of PPAR-Γ ligands and their very low toxicity made them candidates for use in combination with chemotherapeutic drug.