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Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade

Lue, H-W, Podolak, J, Kolahi, K, Cheng, L, Rao, S, Garg, D, Xue, C-H, Rantala, J, Tyner, J, Thornburg, K, Martinez-Acevedo, A, Liu, J-J, Amling, C, Truillet, C, Evans, M, O'Donnell, Valerie, Nomura, D, Drake, J, Ritz, A and Thomas, G 2017. Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade. Genes and Development 31 , pp. 2067-2084. 10.1101/gad.305292.117

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Abstract

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 co-treatment strategies to override this survival advantage.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Cold Spring Harbor Laboratory Press
ISSN: 0890-9369
Date of First Compliant Deposit: 27 October 2017
Date of Acceptance: 26 October 2017
Last Modified: 28 Jan 2018 00:18
URI: http://orca.cf.ac.uk/id/eprint/106007

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