IGF1 promotes resistance to apoptosis in melanoma cells through an increased expression of BCL2, BCL-X(L), and survivin.
IGF1 plays a key role in the development and growth of multiple tumors and in the prevention of apoptosis. In melanoma cells, IGF1 has been shown to mediate resistance to anoikis-induced apoptosis. However, the effect of IGF1 on other proapoptotic stimuli has never been reported. Further, the molecular mechanisms by which IGF1 mediates its prosurvival properties in melanoma cells remain unknown. Here, we demonstrate that IGF1 impairs the onset of tumor necrosis factor-related apoptosis-inducing ligand and staurosporine-induced apoptosis in melanoma cells expressing either wild-type or oncogenic B-Raf. Further, we show that IGF1 inhibits mitochondrial damage that occurs during apoptosis, thereby indicating that IGF1 acts at the level of mitochondria to mediate its antiapoptotic stimuli. Accordingly, IGF1 increases the mRNA levels and protein expression of antiapoptotic members of the BCL2 family--BCL2 and BCL-X(L)--and that of the inhibitor of apoptosis protein, survivin. Further, their specific silencing by small interfering RNA prevents the protective effect of IGF1. These findings therefore delineate the molecular mechanisms by which IGF1 mediates its prosurvival properties and provide a basis for clinical strategies designed to neutralize IGF1 or its target genes.
Hilmi
Caroline
C
Institut National de la Santé et de la Recherche Médicale U597, Biologie et Pathologie des cellules mélanocytaires: de la pigmentation cutanée au mélanome, Nice, France.
Larribere
Lionel
L
Giuliano
Sandy
S
Bille
Karine
K
Ortonne
Jean-Paul
JP
Ballotti
Robert
R
Bertolotto
Corine
C
D017209:Apoptosis; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism*
C107489:BIRC5 protein, human; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; D051020:bcl-X Protein; D007334:Insulin-Like Growth Factor I; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019311:Staurosporine