title: Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress.
abstract: Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. Remarkably, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and the agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy.
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, New South Wales, Australia. Department of Molecular Biology, Shanxi Cancer Hospital and Institute, The Affiliated Cancer Hospital of Shanxi Medical University, Shanxi, China.
authors.forename: Chun Yan
authors.initials: CY
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, New South Wales, Australia. Department of Molecular Biology, Shanxi Cancer Hospital and Institute, The Affiliated Cancer Hospital of Shanxi Medical University, Shanxi, China.
authors.forename: Su Tang
authors.initials: ST
authors.lastname: Guo
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, New South Wales, Australia.
authors.forename: Jia Yu
authors.initials: JY
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, New South Wales, Australia.
authors.forename: Fen
authors.initials: F
authors.lastname: Liu
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, New South Wales, Australia.
authors.forename: Hamed
authors.initials: H
authors.lastname: Yari
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, New South Wales, Australia.
authors.forename: Xu Guang
authors.initials: XG
authors.lastname: Yan
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, New South Wales, Australia. Xu.Zhang@newcastle.edu.au Chenchen.Jiang@newcastle.edu.au.
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia. Xu.Zhang@newcastle.edu.au Chenchen.Jiang@newcastle.edu.au.
authors.forename: Chen Chen
authors.initials: CC
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015870:Gene Expression; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012118:Resorcinols / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D000071717:X-Box Binding Protein 1 / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C096820:BIK protein, human; D000072224:Bcl-2-Like Protein 11; D000091342:Endoplasmic Reticulum Chaperone BiP; D018841:HSP90 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D007555:Isoxazoles; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D012118:Resorcinols; D000071717:X-Box Binding Protein 1; D016283:Proto-Oncogene Proteins p21(ras)