Growth factor-antagonized rexinoid apoptosis involves permissive PPARgamma/RXR heterodimers to activate the intrinsic death pathway by NO.

Date publication

septembre 2009

Auteurs

Membres identifiés du Cancéropôle Est :
Dr GRONEMEYER Hinrich

Tous les auteurs :
Shankaranarayanan P, Rossin A, Khanwalkar H, Alvarez S, Alvarez R, Jacobson A, Nebbioso A, de Lera AR, Altucci L, Gronemeyer H

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/19732722

Résumé

Growth factor (GF) deprivation and/or blocking of cognate signaling can induce apoptosis and is the basis of several cancer treatment paradigms. We observed that RXR agonists (rexinoids) induce apoptosis of tumor cells when GF support is abrogated. This "rexinoid apoptosis" involves activation of both iNOS and eNOS by RXR-PPARgamma and results in production of apoptogenic NO. IGF/EGF-induced IGF receptor 1-mediated MAP kinase blocks rexinoid apoptosis by RXR phosphorylation. Combining rexinoids with the MAPK inhibitor U0126 induced apoptosis in human cancer cells in vitro and ex vivo and blocked xenograft growth in vivo. Our results suggest a regulatory mechanism in which GF signaling antagonizes RXR-PPARgamma-mediated default apoptosis to sustain cell life.

Référence

Cancer Cell. 2009 Sep 8;16(3):220-31