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Pioglitazone inhibits cancer cell growth through STAT3 inhibition and enhanced AIF expression via a PPARγ-independent

Masanobu Tsubaki1, Tomoya Takeda1, Yoshika Tomonari1

  • 1Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka, Japan.

Journal of Cellular Physiology
|October 15, 2017
PubMed

Insights

Pioglitazone induces cancer cell death independently of its known target, peroxisome proliferator-activated receptor gamma (PPARγ). This anti-diabetic drug shows potential as a cancer therapeutic by suppressing STAT3 and Survivin while increasing apoptosis-inducing factor (AIF).

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Pioglitazone, an anti-diabetic drug, targets peroxisome proliferator-activated receptor gamma (PPARγ).
  • PPARγ activation is known to induce cell cycle arrest, differentiation, and apoptosis in cancer cells.
  • The precise mechanisms of pioglitazone's effects on cancer cells remain unclear.

Purpose of the Study:

  • To investigate the mechanism of pioglitazone-induced apoptosis in human cancer cells.
  • To determine if pioglitazone's effects are mediated through PPARγ.
  • To explore pioglitazone's potential as a cancer therapeutic agent.

Main Methods:

  • Treatment of human cancer cells with pioglitazone.
  • Co-treatment with a PPARγ antagonist (GW9662) and a pan-caspase inhibitor (Z-VAD-fmk).
  • Analysis of apoptosis markers, signal transducer and activator of transcription 3 (STAT3) activation, Survivin expression, and apoptosis-inducing factor (AIF) levels.
  • Assessment of pioglitazone's combined effects with cisplatin and oxaliplatin.

Main Results:

  • Pioglitazone induced cancer cell death irrespective of PPARγ expression levels.
  • Neither PPARγ antagonism nor caspase inhibition reversed pioglitazone-induced apoptosis.
  • Pioglitazone suppressed STAT3 activation and Survivin expression while increasing AIF levels.
  • Pioglitazone enhanced the cytotoxicity of cisplatin and oxaliplatin.

Conclusions:

  • Pioglitazone induces apoptosis in cancer cells via a PPARγ-independent pathway.
  • The drug modulates key proteins involved in cell survival and death.
  • Pioglitazone demonstrates potential as an anti-cancer agent, possibly in combination therapies.
Keywords:
AIFPPARγSTAT3pioglitazonesurvivin

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