1. ¹Institut National de la Santé et de la Recherche Médicale (INSERM) U597, Biologie et Pathologie des cellules mélanocytaires: de la pigmentation cutanée au mélanome, Nice, France
2. ²Université de Nice Sophia-Antipolis, UFR de Médecine, Nice, France
3. ³Service de Dermatologie, Hôpital Archet II, CHU Nice, France

Correspondence: Dr Corine Bertolotto, Institut National de la Santé et de la Recherche Médicale (INSERM) U597, Biologie et Physiopathologie de la Peau, 28, Avenue de Valombrose, Nice Cedex 2 6107, France. E-mail: bertolot@unice.fr

Received 19 March 2007; Revised 21 September 2007; Accepted 1 October 2007; Published online 13 December 2007.

Abstract

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.