Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion.
作者： Samuel K. McBrayer , Jennifer M. Rosenbluth , Nobuaki Takahashi , Sabin Dhakal , Vidyasagar Koduri
DOI: 10.1016/J.CMET.2019.01.020
关键词: HSF1 、 Viability assay 、 Glutathione 、 Cell biology 、 Oxidative stress 、 Programmed cell death 、 Cancer cell 、 Unfolded protein response 、 Cancer 、 Chemistry
摘要: Cells are subjected to oxidative stress during the initiation and progression of tumors, this imposes selective pressure for cancer cells adapt mechanisms tolerate these conditions. Here, we examined dependency on glutathione (GSH), most abundant cellular antioxidant. While cell lines displayed a broad range sensitivities inhibition GSH synthesis, majority were resistant depletion. To identify pathways required resistance, carried out genetic pharmacologic screens. Both approaches revealed that deubiquitinating enzymes (DUBs) sensitizes Inhibition in combination with DUB inhibition, led an accumulation polyubiquitinated proteins, induction proteotoxic stress, death. These results indicate depletion renders dependent activity maintain protein homeostasis viability reveal potentially exploitable vulnerability therapy.
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