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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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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. |
format | Online Article Text |
id | pubmed-4695048 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
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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