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

Isaac S. Harris, Jennifer E. Endress, Jonathan L. Coloff, Laura M. Selfors, Samuel K. McBrayer, Jennifer M. Rosenbluth, Nobuaki Takahashi, Sabin Dhakal, Vidyasagar Koduri, Matthew G. Oser, Nathan J. Schauer, Laura M. Doherty, Andrew L. Hong, Yun Pyo Kang, Scott T. Younger, John G. Doench, William C. Hahn, Sara J. Buhrlage, Gina M. DeNicola, William G. KaelinJoan S. Brugge

Research output: Contribution to journalArticle

6 Citations (Scopus)

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. Tumor initiation and progression lead to highly oxidative stress conditions. Harris et al. show that upon glutathione depletion, cancer cells rely on deubiquitinating enzymes to maintain protein homeostasis and cell viability. Combined inhibition of deubiquitinases and glutathione synthesis leads to proteotoxic and ER stress and cell death.

Original languageEnglish (US)
Pages (from-to)1166-1181.e6
JournalCell Metabolism
Volume29
Issue number5
DOIs
StatePublished - May 7 2019
Externally publishedYes

Fingerprint

Glutathione
Cell Survival
Homeostasis
Neoplasms
Proteins
Oxidative Stress
Cell Death
Deubiquitinating Enzymes
Antioxidants
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Harris, I. S., Endress, J. E., Coloff, J. L., Selfors, L. M., McBrayer, S. K., Rosenbluth, J. M., ... Brugge, J. S. (2019). Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion. Cell Metabolism, 29(5), 1166-1181.e6. https://doi.org/10.1016/j.cmet.2019.01.020

Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion. / Harris, Isaac S.; Endress, Jennifer E.; Coloff, Jonathan L.; Selfors, Laura M.; McBrayer, Samuel K.; Rosenbluth, Jennifer M.; Takahashi, Nobuaki; Dhakal, Sabin; Koduri, Vidyasagar; Oser, Matthew G.; Schauer, Nathan J.; Doherty, Laura M.; Hong, Andrew L.; Kang, Yun Pyo; Younger, Scott T.; Doench, John G.; Hahn, William C.; Buhrlage, Sara J.; DeNicola, Gina M.; Kaelin, William G.; Brugge, Joan S.

In: Cell Metabolism, Vol. 29, No. 5, 07.05.2019, p. 1166-1181.e6.

Research output: Contribution to journalArticle

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 & Brugge, JS 2019, 'Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion', Cell Metabolism, vol. 29, no. 5, pp. 1166-1181.e6. https://doi.org/10.1016/j.cmet.2019.01.020
Harris, Isaac S. ; Endress, Jennifer E. ; Coloff, Jonathan L. ; Selfors, Laura M. ; McBrayer, Samuel K. ; Rosenbluth, Jennifer M. ; Takahashi, Nobuaki ; Dhakal, Sabin ; Koduri, Vidyasagar ; Oser, Matthew G. ; Schauer, Nathan J. ; Doherty, Laura M. ; Hong, Andrew L. ; Kang, Yun Pyo ; Younger, Scott T. ; Doench, John G. ; Hahn, William C. ; Buhrlage, Sara J. ; DeNicola, Gina M. ; Kaelin, William G. ; Brugge, Joan S. / Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion. In: Cell Metabolism. 2019 ; Vol. 29, No. 5. pp. 1166-1181.e6.
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