Letter

Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer

Received:
Accepted:
Published online:

Abstract

Cancer cells often select for mutations that enhance signalling through pathways that promote anabolic metabolism1. Although the PI(3)K/Akt signalling 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 tumour growth is not well defined. Here we report that in mammary epithelial cells, oncogenic PI(3)K/Akt stimulates glutathione (GSH) biosynthesis by stabilizing and activating NRF2 to upregulate the GSH biosynthetic genes. Increased NRF2 stability is dependent on the Akt-mediated accumulation of p21Cip1/WAF1 and GSK-3β inhibition. Consistently, in human breast tumours, upregulation of NRF2 targets is associated with PI(3)K pathway mutation status and oncogenic Akt activation. Elevated GSH biosynthesis is required for PI(3)K/Akt-driven resistance to oxidative stress, initiation of tumour spheroids, and anchorage-independent growth. Furthermore, inhibition of GSH biosynthesis with buthionine sulfoximine synergizes with cisplatin to selectively induce tumour regression in PI(3)K pathway mutant breast cancer cells, both in vitro and in vivo. Our findings provide insight into GSH biosynthesis as a metabolic vulnerability associated with PI(3)K pathway mutant breast cancers.

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Acknowledgements

We thank J. Brugge, B. Manning, J. Blenis, A. Beck, I. Harris and members of the Toker and Cantley laboratories for suggestions; A. Baldwin (Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, USA), Y. R. Chin (Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, USA) and G. DeNicola (Department of Medicine, Weill Cornell Medical College, USA) for critical reagents; and M. Yuan and S. Breitkopf for technical assistance with mass spectrometry. Research support was derived in part from the National Institutes of Health (R01CA177910 (A.T.), P01CA120964 (J.M.A.), P30CA006516 (J.M.A.), R01GM041890 (L.C.C.)). E.C.L. is a pre-doctoral fellow of the NSF graduate research fellowship programme (NSF DGE1144152). C.A.L. is financially supported in part by the Pancreatic Cancer Action Network as a Pathway to Leadership Fellow and through a Dale F. Frey Breakthrough award from the Damon Runyon Cancer Research Foundation.

Author information

Affiliations

  1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Evan C. Lien
    •  & Alex Toker
  2. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA

    • Costas A. Lyssiotis
  3. Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, USA

    • Costas A. Lyssiotis
  4. Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Ashish Juvekar
    •  & Hai Hu
  5. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • John M. Asara
  6. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • John M. Asara
    •  & Alex Toker
  7. Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA

    • Lewis C. Cantley

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Contributions

E.C.L., C.A.L., L.C.C. and A.T. designed the study and interpreted the results. E.C.L. and A.T. wrote the manuscript. E.C.L. performed the experiments. J.M.A. and C.A.L. assisted with the LC–MS/MS metabolomic studies and data interpretation. A.J. and H.H. assisted with the in vivo xenograft studies.

Competing interests

L.C.C. owns equity in, receives compensation from, and serves on the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals. Agios Pharmaceuticals is identifying metabolic pathways of cancer cells and developing drugs to inhibit such enzymes to disrupt tumour cell growth and survival.

Corresponding author

Correspondence to Alex Toker.

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