Glutathione biosynthesis is a metabolic vulnerability in PI3K/Akt-driven breast cancer

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Glutathione biosynthesis is a metabolic vulnerability in PI3K/Akt-driven breast cancer

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Title: Glutathione biosynthesis is a metabolic vulnerability in PI3K/Akt-driven breast cancer
Author: Lien, Evan C.; Lyssiotis, Costas A.; Juvekar, Ashish; Hu, Hai; Asara, John M.; Cantley, Lewis C.; Toker, Alex

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Citation: Lien, Evan C., Costas A. Lyssiotis, Ashish Juvekar, Hai Hu, John M. Asara, Lewis C. Cantley, and Alex Toker. 2016. “Glutathione biosynthesis is a metabolic vulnerability in PI3K/Akt-driven breast cancer.” Nature cell biology 18 (5): 572-578. doi:10.1038/ncb3341. http://dx.doi.org/10.1038/ncb3341.
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Abstract: Cancer cells often select for mutations that enhance signaling through pathways that promote anabolic metabolism1. Although the PI3K/Akt signaling pathway, which is frequently dysregulated in breast cancer2, is a well-established regulator of central glucose metabolism and aerobic glycolysis3,4, its regulation of other metabolic processes required for tumor growth is not well defined. Here we report that in mammary epithelial cells, oncogenic PI3K/Akt stimulates glutathione (GSH) biosynthesis by stabilizing and activating Nrf2 to up-regulate the GSH biosynthetic genes. Increased Nrf2 stability is dependent on the Akt-mediated accumulation of p21Cip1/WAF1 and GSK-3 inhibition. Consistently, in human breast tumors, up-regulation of Nrf2 targets is associated with PI3K pathway mutation status and oncogenic Akt activation. Elevated GSH biosynthesis is required for PI3K/Akt-driven resistance to oxidative stress, initiation of tumor spheroids, and anchorage-independent growth. Furthermore, inhibition of GSH biosynthesis with buthionine sulfoximine (BSO) synergizes with cisplatin (CDDP) to selectively induce tumor regression in PI3K pathway mutant breast cancer cells, both in vitro and in vivo. Our findings provide insight into GSH biosynthesis as a metabolic vulnerability associated with PI3K pathway mutant breast cancers.
Published Version: doi:10.1038/ncb3341
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848114/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:29408339
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