title: Mutant KRAS Enhances Tumor Cell Fitness by Upregulating Stress Granules.
abstract: There is growing evidence that stress-coping mechanisms represent tumor cell vulnerabilities that may function as therapeutically beneficial targets. Recent work has delineated an integrated stress adaptation mechanism that is characterized by the formation of cytoplasmic mRNA and protein foci, termed stress granules (SGs). Here, we demonstrate that SGs are markedly elevated in mutant KRAS cells following exposure to stress-inducing stimuli. The upregulation of SGs by mutant KRAS is dependent on the production of the signaling lipid molecule 15-deoxy-delta 12,14 prostaglandin J2 (15-d-PGJ2) and confers cytoprotection against stress stimuli and chemotherapeutic agents. The secretion of 15-d-PGJ2 by mutant KRAS cells is sufficient to enhance SG formation and stress resistance in cancer cells that are wild-type for KRAS. Our findings identify a mutant KRAS-dependent cell non-autonomous mechanism that may afford the establishment of a stress-resistant niche that encompasses different tumor subclones. These results should inform the design of strategies to eradicate tumor cell communities.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Elda
authors.initials: E
authors.lastname: Grabocka
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: dafna.bar-sagi@nyumc.org.
authors.forename: Dafna
authors.initials: D
authors.lastname: Bar-Sagi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003594:Cytoplasmic Granules / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D039601:Eukaryotic Initiation Factor-4A / Q000378:metabolism; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; C117307:KRAS protein, human; D039601:Eukaryotic Initiation Factor-4A; D016283:Proto-Oncogene Proteins p21(ras); D015230:Prostaglandin D2
keywords: KRAS; cancer; prostaglandins; stress granules