Growth factor-antagonized rexinoid apoptosis involves permissive PPARgamma/RXR heterodimers to activate the intrinsic death pathway by NO.
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.
Shankaranarayanan
Pattabhiraman
P
Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), BP 10142, 67404 ILLKIRCH CEDEX, C. U. de Strasbourg, France.
Rossin
Aurélie
A
Khanwalkar
Harshal
H
Alvarez
Susana
S
Alvarez
Rosana
R
Jacobson
Annica
A
Nebbioso
Angela
A
de Lera
Angel R
AR
Altucci
Lucia
L
Gronemeyer
Hinrich
H
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
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