title: Growth factor-antagonized rexinoid apoptosis involves permissive PPARgamma/RXR heterodimers to activate the intrinsic death pathway by NO.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), BP 10142, 67404 ILLKIRCH CEDEX, C. U. de Strasbourg, France.
authors.forename: Pattabhiraman
authors.initials: P
authors.lastname: Shankaranarayanan
authors.forename: Aurélie
authors.initials: A
authors.lastname: Rossin
authors.forename: Harshal
authors.initials: H
authors.lastname: Khanwalkar
authors.forename: Susana
authors.initials: S
authors.lastname: Alvarez
authors.forename: Rosana
authors.initials: R
authors.lastname: Alvarez
authors.forename: Annica
authors.initials: A
authors.lastname: Jacobson
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.forename: Angel R
authors.initials: AR
authors.lastname: de Lera
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005822:Genetic Vectors; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D009569:Nitric Oxide / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D011897:Random Allocation; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D009570:Nitriles; D047495:PPAR gamma; D034741:RNA, Small Interfering; D047488:Retinoid X Receptors; C113580:U 0126; D009569:Nitric Oxide