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

Nicholas J Clemons; David S Liu; Cuong P Duong; Wayne A Phillips

doi:10.1080/23723556.2017.1344757

Inhibiting system x_C^- and glutathione biosynthesis - a potential Achilles' heel in mutant-p53 cancers

Mol Cell Oncol. 2017 Jul 5;4(5):e1344757. doi: 10.1080/23723556.2017.1344757. eCollection 2017.

Authors

Nicholas J Clemons^{1

2}, David S Liu^{1

2

3

4}, Cuong P Duong³, Wayne A Phillips^{1

2

3

5}

Affiliations

¹ Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
² Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
³ Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁴ Department of Surgery, Austin Hospital, Heidelberg, Victoria, Australia.
⁵ Department of Surgery (St Vincent's Hospital), The University of Melbourne, Parkville, Victoria, Australia.

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.

Keywords: APR-246; NFE2L2; NRF2; PRIMA-1met; SLC7A11; glutathione (GSH); p53; reactive oxygen species (ROS); system xC−; xCT.