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

• Published in: Cell metabolism Vol. 29; no. 5; pp. 1166 - 1181.e6
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.05.2019
• Subjects: A549 Cells; Aminopyridines - pharmacology; Animals; antioxidants; Antioxidants - metabolism; Buthionine Sulfoximine - pharmacology; cancer; Catalytic Domain - drug effects; Cell Survival - drug effects; deubiquitinase; Deubiquitinating Enzymes - antagonists & inhibitors; Deubiquitinating Enzymes - metabolism; Female; GCLC; Glutamate-Cysteine Ligase - antagonists & inhibitors; Glutamate-Cysteine Ligase - chemistry; Glutamate-Cysteine Ligase - metabolism; glutamate-cysteine ligase catalytic subunit; glutathione; Glutathione - metabolism; heat shock factor 1; high-throughput screening; HSF1; Humans; Mammary Glands, Animal - cytology; Mammary Glands, Human - cytology; MCF-7 Cells; Mice; Mice, Inbred C57BL; Mice, Nude; Organoids - drug effects; oxidative stress; Oxidative Stress - drug effects; Proteostasis - drug effects; proteotoxic stress; Thiocyanates - pharmacology; Tumor Burden - drug effects; Ubiquitinated Proteins - metabolism; unfolded protein response; UPR; Xenograft Model Antitumor Assays; proteotoxic stress; antioxidants; glutathione; high-throughput screening; deubiquitinase; unfolded protein response; GCLC; glutamate-cysteine ligase catalytic subunit; UPR; HSF1; heat shock factor 1; cancer; oxidative stress
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2019.01.020

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. [Display omitted] •Most cancer cell lines are largely insensitive to GSH depletion•Deubiquitinases (DUBs) protect cancer cells upon inhibition of GSH synthesis•Inhibition of DUBs and GSH synthesis causes ER and proteotoxic stress and cell death•Combined targeting of DUBs and GSH blocks tumor growth 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.