RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma
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Florence Laugier1,2, Adeline Finet-Benyair1,2, Jocelyne André1,2, P. Sivaramakrishna Rachakonda3, Rajiv Kumar3, Armand Bensussan1,2, Nicolas Dumaz1,2
1INSERM, U976, Centre de Recherche sur la Peau, Hôpital Saint-Louis, Paris, F-75010, France
2Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France
3Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120, Heidelberg, Germany
Nicolas Dumaz, e-mail: [email protected]
Keywords: RICTOR, PI3K, AKT, melanoma, mTORC2
Received: February 10, 2015 Accepted: August 17, 2015 Published: August 27, 2015
Several studies have highlighted the importance of the PI3K pathway in melanocytes and its frequent over-activation in melanoma. However, little is known about regulation of the PI3K pathway in melanocytic cells. We showed that normal human melanocytes are less sensitive to selective PI3K or mTOR inhibitors than to dual PI3K/mTOR inhibitors. The resistance to PI3K inhibitor was due to a rapid AKT reactivation limiting the inhibitor effect on proliferation. Reactivation of AKT was linked to a feedback mechanism involving the mTORC2 complex and in particular its scaffold protein RICTOR. RICTOR overexpression in melanocytes disrupted the negative feedback, activated the AKT pathway and stimulated clonogenicity highlighting the importance of this feedback to restrict melanocyte proliferation. We found that the RICTOR locus is frequently amplified and overexpressed in melanoma and that RICTOR over-expression in NRAS-transformed melanocytes stimulates their clonogenicity, demonstrating that RICTOR amplification can cooperate with NRAS mutation to stimulate melanoma proliferation. These results show that RICTOR plays a central role in PI3K pathway negative feedback in melanocytes and that its deregulation could be involved in melanoma development.
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