Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma.

The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway promotes melanoma tumor growth and survival while suppressing autophagy, a catabolic process through which cells collect and recycle cellular components to sustain energy homeostasis in starvation. Conversely...

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Autores principales:	Xiaoqi Xie, Eileen P White, Janice M Mehnert
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/84f0e283748e4d67bc8d9c5dac538f48
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spelling	oai:doaj.org-article:84f0e283748e4d67bc8d9c5dac538f482021-11-18T07:59:28ZCoordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma.1932-620310.1371/journal.pone.0055096https://doaj.org/article/84f0e283748e4d67bc8d9c5dac538f482013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23383069/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway promotes melanoma tumor growth and survival while suppressing autophagy, a catabolic process through which cells collect and recycle cellular components to sustain energy homeostasis in starvation. Conversely, inhibitors of the PI3K/AKT/mTOR pathway, in particular the mTOR inhibitor temsirolimus (CCI-779), induce autophagy, which can promote tumor survival and thus, these agents potentially limit their own efficacy. We hypothesized that inhibition of autophagy in combination with mTOR inhibition would block this tumor survival mechanism and hence improve the cytotoxicity of mTOR inhibitors in melanoma. Here we found that melanoma cell lines of multiple genotypes exhibit high basal levels of autophagy. Knockdown of expression of the essential autophagy gene product ATG7 resulted in cell death, indicating that survival of melanoma cells is autophagy-dependent. We also found that the lysosomotropic agent and autophagy inhibitor hydroxychloroquine (HCQ) synergizes with CCI-779 and led to melanoma cell death via apoptosis. Combination treatment with CCI-779 and HCQ suppressed melanoma growth and induced cell death both in 3-dimensional (3D) spheroid cultures and in tumor xenografts. These data suggest that coordinate inhibition of the mTOR and autophagy pathways promotes apoptosis and could be a new therapeutic paradigm for the treatment of melanoma.Xiaoqi XieEileen P WhiteJanice M MehnertPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 1, p e55096 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xiaoqi Xie Eileen P White Janice M Mehnert Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma.
description	The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway promotes melanoma tumor growth and survival while suppressing autophagy, a catabolic process through which cells collect and recycle cellular components to sustain energy homeostasis in starvation. Conversely, inhibitors of the PI3K/AKT/mTOR pathway, in particular the mTOR inhibitor temsirolimus (CCI-779), induce autophagy, which can promote tumor survival and thus, these agents potentially limit their own efficacy. We hypothesized that inhibition of autophagy in combination with mTOR inhibition would block this tumor survival mechanism and hence improve the cytotoxicity of mTOR inhibitors in melanoma. Here we found that melanoma cell lines of multiple genotypes exhibit high basal levels of autophagy. Knockdown of expression of the essential autophagy gene product ATG7 resulted in cell death, indicating that survival of melanoma cells is autophagy-dependent. We also found that the lysosomotropic agent and autophagy inhibitor hydroxychloroquine (HCQ) synergizes with CCI-779 and led to melanoma cell death via apoptosis. Combination treatment with CCI-779 and HCQ suppressed melanoma growth and induced cell death both in 3-dimensional (3D) spheroid cultures and in tumor xenografts. These data suggest that coordinate inhibition of the mTOR and autophagy pathways promotes apoptosis and could be a new therapeutic paradigm for the treatment of melanoma.
format	article
author	Xiaoqi Xie Eileen P White Janice M Mehnert
author_facet	Xiaoqi Xie Eileen P White Janice M Mehnert
author_sort	Xiaoqi Xie
title	Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma.
title_short	Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma.
title_full	Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma.
title_fullStr	Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma.
title_full_unstemmed	Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma.
title_sort	coordinate autophagy and mtor pathway inhibition enhances cell death in melanoma.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/84f0e283748e4d67bc8d9c5dac538f48
work_keys_str_mv	AT xiaoqixie coordinateautophagyandmtorpathwayinhibitionenhancescelldeathinmelanoma AT eileenpwhite coordinateautophagyandmtorpathwayinhibitionenhancescelldeathinmelanoma AT janicemmehnert coordinateautophagyandmtorpathwayinhibitionenhancescelldeathinmelanoma
_version_	1718422678982885376

Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma.

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