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Growth factor-antagonized rexinoid apoptosis involves permissive PPARgamma/RXR heterodimers to activate the intrinsic

Pattabhiraman Shankaranarayanan1, Aurélie Rossin, Harshal Khanwalkar

  • 1Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), BP 10142, 67404 ILLKIRCH CEDEX, C. U. de Strasbourg, France.

Cancer Cell
|September 8, 2009
PubMed

Insights

RXR agonists induce tumor cell death when growth factors are absent, activating nitric oxide production. Combining rexinoids with a MAPK inhibitor enhances this apoptosis and inhibits tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Growth factor (GF) deprivation is a key strategy in cancer treatment, inducing apoptosis.
  • Retinoid X receptor (RXR) agonists, or rexinoids, show potential in cancer therapy.
  • Understanding molecular mechanisms of apoptosis is crucial for developing effective cancer treatments.

Purpose of the Study:

  • To investigate the role of RXR agonists in inducing apoptosis in tumor cells under conditions of GF deprivation.
  • To elucidate the signaling pathways involved in "rexinoid apoptosis" and its regulation by GF signaling.
  • To evaluate the therapeutic potential of combining rexinoids with MAPK inhibitors for cancer treatment.

Main Methods:

  • Induction of apoptosis in tumor cells using RXR agonists with and without growth factors.
  • Analysis of nitric oxide (NO) production via inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS).
  • Investigating the role of RXR-PPARgamma activation and MAP kinase (MAPK) signaling.
  • In vitro, ex vivo, and in vivo studies combining rexinoids with the MAPK inhibitor U0126.

Main Results:

  • RXR agonists induce apoptosis in tumor cells lacking GF support, a process termed "rexinoid apoptosis".
  • This apoptosis is mediated by RXR-PPARgamma activation, leading to apoptogenic NO production.
  • Insulin-like growth factor (IGF)/Epidermal growth factor (EGF)-induced IGF receptor 1-mediated MAPK signaling blocks rexinoid apoptosis through RXR phosphorylation.
  • Combination therapy with rexinoids and U0126 induced apoptosis in human cancer cells and inhibited xenograft tumor growth.

Conclusions:

  • GF signaling antagonizes RXR-PPARgamma-mediated default apoptosis, thereby sustaining cell survival.
  • Targeting this regulatory mechanism by combining rexinoids with MAPK inhibitors represents a promising therapeutic strategy for cancer.
  • The findings provide insights into a novel pathway for cancer treatment by modulating apoptosis.

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