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Cell Metab. 2019 May 7;29(5):1166-1181.e6. doi: 10.1016/j.cmet.2019.01.020. Epub 2019 Feb 21.

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

Author information

1
Ludwig Cancer Center, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
2
Harvard Medical School, Boston, MA 02115, USA.
3
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
4
Ludwig Cancer Center, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA.
5
Dana-Farber Cancer Institute, Boston, MA 02115, USA; Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA.
6
Department of Cancer Physiology, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
7
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA.
8
Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA; Brigham and Women's Hospital, Boston, MA 02115, USA.
9
Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA.
10
Ludwig Cancer Center, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: joan_brugge@hms.harvard.edu.

Abstract

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.

KEYWORDS:

GCLC; HSF1; UPR; antioxidants; cancer; deubiquitinase; glutamate-cysteine ligase catalytic subunit; glutathione; heat shock factor 1; high-throughput screening; oxidative stress; proteotoxic stress; unfolded protein response

PMID:
30799286
PMCID:
PMC6506399
[Available on 2020-05-07]
DOI:
10.1016/j.cmet.2019.01.020

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