title: The integrated stress response and proteotoxicity in cancer therapy.
abstract: A variety of different forms of cellular stress can cause protein misfolding and aggregation and proteotoxicity. The cytoprotective response to proteotoxicity is termed the integrated stress response and involves 4 distinct serine/threonine protein kinases that converge on the translation initiation factor eIF2α, resulting in phosphorylation at S51, cell cycle arrest, and a general inhibition of global protein synthesis. Phosphorylation of eIF2α also promotes translation of ATF4 and the expression of ATF4 target genes that ameliorate proteotoxic stress but can also promote apoptosis. This mini review provides a general overview of these mechanisms and discusses how the inter-tumor heterogeneity that involves them affects sensitivity and resistance to proteasome inhibitors, a new class of cancer therapeutics that promotes tumor cell killing via proteotoxic stress.
authors.affiliation: Johns Hopkins Greenberg Bladder Cancer Institute, Brady Urological Institute, 600 North Wolfe Street, Baltimore, MD 21287, United States. Electronic address: djmcconkey@jhmi.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000628:therapy*; D010766:Phosphorylation; D061988:Proteasome Inhibitors / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D057165:Proteostasis Deficiencies / Q000378:metabolism / Q000628:therapy; D013312:Stress, Physiological; D019892:eIF-2 Kinase
chemical_list: D015852:Eukaryotic Initiation Factor-2; D061988:Proteasome Inhibitors; D051701:Activating Transcription Factor 4; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase
keywords: Autophagy; ER stress; HRI; PERK; Protein aggregates; Translation; Unfolded protein response