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Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade

There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K–AKT–mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restr...

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Autores principales: Lue, Hui-wen, Podolak, Jennifer, Kolahi, Kevin, Cheng, Larry, Rao, Soumya, Garg, Devin, Xue, Chang-Hui, Rantala, Juha K., Tyner, Jeffrey W., Thornburg, Kent L., Martinez-Acevedo, Ann, Liu, Jen-Jane, Amling, Christopher L., Truillet, Charles, Louie, Sharon M., Anderson, Kimberly E., Evans, Michael J., O'Donnell, Valerie B., Nomura, Daniel K., Drake, Justin M., Ritz, Anna, Thomas, George V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733498/
https://www.ncbi.nlm.nih.gov/pubmed/29138276
http://dx.doi.org/10.1101/gad.305292.117
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author Lue, Hui-wen
Podolak, Jennifer
Kolahi, Kevin
Cheng, Larry
Rao, Soumya
Garg, Devin
Xue, Chang-Hui
Rantala, Juha K.
Tyner, Jeffrey W.
Thornburg, Kent L.
Martinez-Acevedo, Ann
Liu, Jen-Jane
Amling, Christopher L.
Truillet, Charles
Louie, Sharon M.
Anderson, Kimberly E.
Evans, Michael J.
O'Donnell, Valerie B.
Nomura, Daniel K.
Drake, Justin M.
Ritz, Anna
Thomas, George V.
author_facet Lue, Hui-wen
Podolak, Jennifer
Kolahi, Kevin
Cheng, Larry
Rao, Soumya
Garg, Devin
Xue, Chang-Hui
Rantala, Juha K.
Tyner, Jeffrey W.
Thornburg, Kent L.
Martinez-Acevedo, Ann
Liu, Jen-Jane
Amling, Christopher L.
Truillet, Charles
Louie, Sharon M.
Anderson, Kimberly E.
Evans, Michael J.
O'Donnell, Valerie B.
Nomura, Daniel K.
Drake, Justin M.
Ritz, Anna
Thomas, George V.
author_sort Lue, Hui-wen
collection PubMed
description There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K–AKT–mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this, we observed significantly increased lipid droplets, with subsequent mobilization to mitochondria. These changes were abrogated in cells deficient for the essential autophagy gene ATG5. Accordingly, inhibition of PLA2 significantly decreased lipid droplets, decreased oxidative phosphorylation, and increased apoptosis. Together, these results describe how treatment-induced autophagy provides nutrients for cancer cell survival and identifies novel cotreatment strategies to override this survival advantage.
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spelling pubmed-57334982018-04-15 Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade Lue, Hui-wen Podolak, Jennifer Kolahi, Kevin Cheng, Larry Rao, Soumya Garg, Devin Xue, Chang-Hui Rantala, Juha K. Tyner, Jeffrey W. Thornburg, Kent L. Martinez-Acevedo, Ann Liu, Jen-Jane Amling, Christopher L. Truillet, Charles Louie, Sharon M. Anderson, Kimberly E. Evans, Michael J. O'Donnell, Valerie B. Nomura, Daniel K. Drake, Justin M. Ritz, Anna Thomas, George V. Genes Dev Research Paper There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K–AKT–mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this, we observed significantly increased lipid droplets, with subsequent mobilization to mitochondria. These changes were abrogated in cells deficient for the essential autophagy gene ATG5. Accordingly, inhibition of PLA2 significantly decreased lipid droplets, decreased oxidative phosphorylation, and increased apoptosis. Together, these results describe how treatment-induced autophagy provides nutrients for cancer cell survival and identifies novel cotreatment strategies to override this survival advantage. Cold Spring Harbor Laboratory Press 2017-10-15 /pmc/articles/PMC5733498/ /pubmed/29138276 http://dx.doi.org/10.1101/gad.305292.117 Text en © 2017 Lue et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Lue, Hui-wen
Podolak, Jennifer
Kolahi, Kevin
Cheng, Larry
Rao, Soumya
Garg, Devin
Xue, Chang-Hui
Rantala, Juha K.
Tyner, Jeffrey W.
Thornburg, Kent L.
Martinez-Acevedo, Ann
Liu, Jen-Jane
Amling, Christopher L.
Truillet, Charles
Louie, Sharon M.
Anderson, Kimberly E.
Evans, Michael J.
O'Donnell, Valerie B.
Nomura, Daniel K.
Drake, Justin M.
Ritz, Anna
Thomas, George V.
Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade
title Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade
title_full Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade
title_fullStr Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade
title_full_unstemmed Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade
title_short Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade
title_sort metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733498/
https://www.ncbi.nlm.nih.gov/pubmed/29138276
http://dx.doi.org/10.1101/gad.305292.117
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