RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma

Florence Laugier; Adeline Finet-Benyair; Jocelyne André; P Sivaramakrishna Rachakonda; Rajiv Kumar; Armand Bensussan; Nicolas Dumaz

doi:10.18632/oncotarget.4866

RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma

Oncotarget. 2015 Sep 29;6(29):28120-31. doi: 10.18632/oncotarget.4866.

Authors

Florence Laugier^{1

2}, Adeline Finet-Benyair^{1

2}, Jocelyne André^{1

2}, P Sivaramakrishna Rachakonda³, Rajiv Kumar³, Armand Bensussan^{1

2}, Nicolas Dumaz^{1

2}

Affiliations

¹ INSERM, U976, Centre de Recherche sur la Peau, Hôpital Saint-Louis, Paris, F-75010, France.
² Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France.
³ Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120, Heidelberg, Germany.

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.

Keywords: AKT; PI3K; RICTOR; mTORC2; melanoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Cell Line
Cell Line, Tumor
Cell Proliferation / drug effects
Cells, Cultured
GTP Phosphohydrolases / genetics
GTP Phosphohydrolases / metabolism
Humans
Imidazoles / pharmacology
Melanocytes / drug effects
Melanocytes / metabolism*
Melanoma / genetics
Melanoma / metabolism*
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mutation
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins c-akt / metabolism*
Pyrimidines / pharmacology
Rapamycin-Insensitive Companion of mTOR Protein
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / metabolism
Triazines / pharmacology

Substances

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
Bridged Bicyclo Compounds, Heterocyclic
Carrier Proteins
Imidazoles
Membrane Proteins
OSI 027
Phosphoinositide-3 Kinase Inhibitors
Pyrimidines
RICTOR protein, human
Rapamycin-Insensitive Companion of mTOR Protein
Triazines
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
GTP Phosphohydrolases
NRAS protein, human