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

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 in...

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Autores principales: Laugier, Florence, Finet-Benyair, Adeline, André, Jocelyne, Rachakonda, P. Sivaramakrishna, Kumar, Rajiv, Bensussan, Armand, Dumaz, Nicolas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695048/
https://www.ncbi.nlm.nih.gov/pubmed/26356562
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author Laugier, Florence
Finet-Benyair, Adeline
André, Jocelyne
Rachakonda, P. Sivaramakrishna
Kumar, Rajiv
Bensussan, Armand
Dumaz, Nicolas
author_facet Laugier, Florence
Finet-Benyair, Adeline
André, Jocelyne
Rachakonda, P. Sivaramakrishna
Kumar, Rajiv
Bensussan, Armand
Dumaz, Nicolas
author_sort Laugier, Florence
collection PubMed
description 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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spelling pubmed-46950482016-01-20 RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma Laugier, Florence Finet-Benyair, Adeline André, Jocelyne Rachakonda, P. Sivaramakrishna Kumar, Rajiv Bensussan, Armand Dumaz, Nicolas Oncotarget Research Paper 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. Impact Journals LLC 2015-08-27 /pmc/articles/PMC4695048/ /pubmed/26356562 Text en Copyright: © 2015 Laugier et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Laugier, Florence
Finet-Benyair, Adeline
André, Jocelyne
Rachakonda, P. Sivaramakrishna
Kumar, Rajiv
Bensussan, Armand
Dumaz, Nicolas
RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma
title RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma
title_full RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma
title_fullStr RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma
title_full_unstemmed RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma
title_short RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma
title_sort rictor involvement in the pi3k/akt pathway regulation in melanocytes and melanoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695048/
https://www.ncbi.nlm.nih.gov/pubmed/26356562
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