Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion.

Graphical abstract from Harris, et al (2019).

Copyright © 2019 Elsevier B.V.

Harris IS, Endress JE, Coloff JL, Selfors LM, McBrayer SK, Rosenbluth JM, Takahashi N, Dhakal S, Koduri V, Oser MG, Schauer NJ, Doherty LM, Hong AL, Kang YP, Younger ST, Doench JG, Hahn WC, Buhrlage SJ, DeNicola GM, Kaelin WG Jr, Brugge JS.

Cell Metabolism

February 13, 2019

Cells are subjected to oxidative stress during the initiation and progression of tumors, and this imposes selective pressure for cancer cells to adapt mechanisms to tolerate these conditions. Here, we examined the dependency of cancer cells on glutathione (GSH), the most abundant cellular antioxidant. While cancer cell lines displayed a broad range of sensitivities to inhibition of GSH synthesis, the majority were resistant to GSH depletion. To identify cellular pathways required for this resistance, we carried out genetic and pharmacologic screens. Both approaches revealed that inhibition of deubiquitinating enzymes (DUBs) sensitizes cancer cells to GSH depletion. Inhibition of GSH synthesis, in combination with DUB inhibition, led to an accumulation of polyubiquitinated proteins, induction of proteotoxic stress, and cell death. These results indicate that depletion of GSH renders cancer cells dependent on DUB activity to maintain protein homeostasis and cell viability and reveal a potentially exploitable vulnerability for cancer therapy.

Last updated: March 01, 2019