title: RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma.
abstract: 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.
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, Hôpital Saint-Louis, Paris, F-75010, France.|Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Laugier
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, Hôpital Saint-Louis, Paris, F-75010, France.|Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Finet-Benyair
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, Hôpital Saint-Louis, Paris, F-75010, France.|Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: André
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120, Heidelberg, Germany.
authors.forename: P Sivaramakrishna
authors.initials: PS
authors.lastname: Rachakonda
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120, Heidelberg, Germany.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, Hôpital Saint-Louis, Paris, F-75010, France.|Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France.
authors.forename: Armand
authors.initials: A
authors.lastname: Bensussan
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, Hôpital Saint-Louis, Paris, F-75010, France.|Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dumaz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002352:Carrier Proteins; D020558:GTP Phosphohydrolases; D007093:Imidazoles; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases; D014227:Triazines; C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; C568605:OSI 027; C492571:RICTOR protein, human; C579846:NRAS protein, human
keywords: AKT; PI3K; RICTOR; mTORC2; melanoma