Inhibiting system xC − and glutathione biosynthesis–a potential Achilles' heel in mutant-p53 cancers

NJ Clemons; DS Liu; CP Duong; WA Phillips

Journal article

Inhibiting system xC − and glutathione biosynthesis–a potential Achilles' heel in mutant-p53 cancers

NJ Clemons, DS Liu, CP Duong, WA Phillips

Molecular and Cellular Oncology | Published : 2017

DOI: 10.1080/23723556.2017.1344757

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Abstract

Effective therapeutic strategies to target mutant tumor protein p53 (TP53, best known as p53) cancers remain an unmet medical need. We found that mutant p53 impairs the function of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, commonly known as NRF2), suppresses solute carrier family 7 member 11 (SLC7A11) expression, and diminishes cellular glutamate/cystine exchange. This decreases glutathione biosynthesis, resulting in redox imbalance. Mutant p53 tumors are thus inherently susceptible to further perturbations of the SLC7A11/glutathione axis.

University of Melbourne Researchers

Nicholas Clemons Author

David Liu Author

Cuong Duong Author

Wayne Phillips Author

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Grants

Awarded by Victorian Cancer Agency

Funding Acknowledgements

This work was supported by a National Health and Medical Research Council (NHMRC) of Australia Centers for Research Excellence Grant # 1040947 (WAP) and Project Grant # 1120293 (WAP and NJC), a Translational Research Project Grant (TRP15012) from the Victorian Government Department of Health and Human Services through the Victorian Cancer Agency (WAP, NJC and CDP), and a Peter MacCallum Cancer Foundation New Investigator grant (DSL). NJC is supported by a Victorian Cancer Agency Fellowship (MCRF16002). DSL was supported by the Royal Australasian College of Surgeons Foundation for Surgery John Loewenthal, Reg Worcester and Eric Bishop Fellowships, Cancer Therapeutics Scholarship (Cancer Therapeutics CRC) and NHMRC Postgraduate Research Scholarship.