Phenotypic assays identify azoramide as a small-molecule modulator of the unfolded protein response with antidiabetic activity

Science Translational Medicine

Volumn 7, Issue 292, 2015, Pages

  Fu, Suneng ^a,b   Yalcin, Abdullah ^a   Lee, Grace Y ^a   Li, Ping ^a   Fan, Jason ^a,d   Arruda, Ana Paula ^a   Pers, Benedicte M ^a   Yilmaz, Mustafa ^a   Eguchi, Kosei ^a   Hotamisligil, Gökhan S ^a,c  

^a HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^b TSINGHUA UNIVERSITY   (China)

^c MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^d Och Spine at New York Presbyterian Hospitals   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIDIABETIC AGENT; AZORAMIDE; CHAPERONE; ENZYME INHIBITOR; GSK 2606414; N [2 [2 [4 CHLOROPHENYL]THIAZOL 4 Y]ETHYL]BUTANAMIDE; UNCLASSIFIED DRUG; AMIDE; CALCIUM; GLUCOSE; INSULIN; LUCIFERASE; N-(2-(2-(4-CHLOROPHENYL)-1,3-THIAZOL-4-YL)ETHYL)BUTANAMIDE; THIAZOLE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIDIABETIC ACTIVITY; ARTICLE; ASSAY; CALCIUM HOMEOSTASIS; CALCIUM SIGNALING; CELL FUNCTION; CELL PROTECTION; CONTROLLED STUDY; DEGENERATIVE DISEASE; DIABETES MELLITUS; DRUG DESIGN; DRUG EFFICACY; DRUG STRUCTURE; ENDOPLASMIC RETICULUM; ENDOPLASMIC RETICULUM STRESS; GLUCOSE METABOLISM; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; INFLAMMATION; INSULIN SENSITIVITY; LIPID METABOLISM; MALE; MOUSE MODEL; NEOPLASM; NONHUMAN; OBESITY; PANCREAS ISLET BETA CELL; PHENOTYPIC ASSAY; PRIORITY JOURNAL; PROTEIN FOLDING; PROTEIN METABOLISM; UNFOLDED PROTEIN RESPONSE; ANIMAL; CELL SURVIVAL; DIET; DRUG EFFECTS; ENERGY METABOLISM; GENETICS; HEK293 CELL LINE; HOMEOSTASIS; METABOLISM; METABOLOME; MOUSE MUTANT; PATHOLOGY; PHENOTYPE; PROCEDURES; REPORTER GENE; SECRETION (PROCESS); WEIGHT REDUCTION;

AMIDES; ANIMALS; CALCIUM; CELL SURVIVAL; CYTOPROTECTION; DIET; ENDOPLASMIC RETICULUM; ENDOPLASMIC RETICULUM STRESS; ENERGY METABOLISM; GENES, REPORTER; GLUCOSE; HEK293 CELLS; HIGH-THROUGHPUT SCREENING ASSAYS; HOMEOSTASIS; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; INSULIN-SECRETING CELLS; LUCIFERASES; METABOLOME; MICE, OBESE; MOLECULAR CHAPERONES; OBESITY; PHENOTYPE; PROTEIN FOLDING; THIAZOLES; UNFOLDED PROTEIN RESPONSE; WEIGHT LOSS;

EID: 84931345859     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aaa9134     Document Type: Article

References (71)

1. K. A. Dill, S. B. Ozkan, M. S. Shell, T. R. Weikl, The protein folding problem. Annu. Rev. Biophys. 37, 289-316 (2008).
2. B. Bukau, J. Weissman, A. Horwich, Molecular chaperones and protein quality control. Cell 125, 443-451 (2006).
3. C. Sidrauski, R. Chapman, P. Walter, The unfolded protein response: An intracellular signalling pathway with many surprising features. Trends Cell Biol. 8, 245-249 (1998).
4. K. Mori, Signalling pathways in the unfolded protein response: Development from yeast to mammals. J. Biochem. 146, 743-750 (2009).
5. K. Haze, H. Yoshida, H. Yanagi, T. Yura, K. Mori, Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 10, 3787-3799 (1999).
6. W. Tirasophon, K. Lee, B. Callaghan, A. Welihinda, R. J. Kaufman, The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response. Genes Dev. 14, 2725-2736 (2000).
7. H. P. Harding, Y. Zhang, D. Ron, Protein translation and folding are coupled by an endoplasmicreticulum-resident kinase. Nature 397,271-274 (1999).
8. D. Ron, S. R. Hubbard, How IRE1 reacts to ER stress. Cell 132, 24-26 (2008).
9. J.P.Upton,L.Wang,D.Han,E.S.Wang,N.E.Huskey,L.Lim,M.Truitt,M.T.McManus, D. Ruggero, A. Goga, F. R. Papa, S. A. Oakes, IRE1a cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 338, 818-822 (2012).
10. C. Sidrauski, P. Walter, The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 90, 1031-1039 (1997).
11. K. Yamamoto, H. Yoshida, K. Kokame, R. J. Kaufman, K. Mori, Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J. Biochem. 136, 343-350 (2004).
12. J. Shen, X. Chen, L. Hendershot, R. Prywes, ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev. Cell 3, 99-111 (2002).
13. J. Shen, E. L. Snapp, J. Lippincott-Schwartz, R. Prywes, Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response. Mol. Cell. Biol. 25, 921-932 (2005).
14. S. Bernales, F. R. Papa, P. Walter, Intracellular signaling by the unfolded protein response. Annu. Rev. Cell Dev. Biol. 22, 487-508 (2006).
15. S. Fu, S. M. Watkins, G. S. Hotamisligil, The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab. 15, 623-634 (2012).
16. P. Walter, D. Ron, The unfolded protein response: From stress pathway to homeostatic regulation. Science 334, 1081-1086 (2011).
17. S.Fu,L.Yang,P.Li,O.Hofmann,L.Dicker,W.Hide,X.Lin,S.M.Watkins,A.R.Ivanov, G. S. Hotamisligil, Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473, 528-531 (2011).
18. T. Nakamura, M. Furuhashi, P. Li, H. Cao, G. Tuncman, N. Sonenberg, C. Z. Gorgun, G. S. Hotamisligil, Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell 140,338-348 (2010).
19. U. Ozcan, Q. Cao, E. Yilmaz, A. H. Lee, N. N. Iwakoshi, E. Ozdelen, G. Tuncman, C. Görgün, L. H. Glimcher, G. S. Hotamisligil, Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457-461 (2004).
20. G. S. Hotamisligil, Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900-917 (2010).
21. I. Tabas, D. Ron, Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat. Cell Biol. 13, 184-190 (2011).
22. X. Z. Wang, B. Lawson, J. W. Brewer, H. Zinszner, A. Sanjay, L. J. Mi, R. Boorstein, G. Kreibich, L. M. Hendershot, D. Ron, Signals from the stressed endoplasmic reticulum induce C/EBPhomologous protein (CHOP/GADD153). Mol. Cell. Biol. 16, 4273-4280 (1996).
23. H. J. Clarke, J. E. Chambers, E. Liniker, S. J. Marciniak, Endoplasmic reticulum stress in malignancy. Cancer Cell 25, 563-573 (2014).
24. S. Wang, R. J. Kaufman, The impact of the unfolded protein response on human disease. J. Cell Biol. 197, 857-867 (2012).
25. G. S. Hotamisligil, Endoplasmic reticulum stress and atherosclerosis. Nat. Med. 16, 396-399 (2010).
26. S. J. Marciniak, D. Ron, Endoplasmic reticulum stress signaling in disease. Physiol. Rev. 86, 1133-1149 (2006).
27. S. S. Cao, R. J. Kaufman, Targeting endoplasmic reticulum stress in metabolic disease. Expert Opin. Ther. Targets 17, 437-448 (2013).
28. U.Ozcan,E.Yilmaz,L.Ozcan,M.Furuhashi,E.Vaillancourt,R.O.Smith,C.Z.Görgün, G. S. Hotamisligil, Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313, 1137-1140 (2006).
29. H. W. Park, H. Park, S. H. Ro, I. Jang, I. A. Semple, D. N. Kim, M. Kim, M. Nam, D. Zhang, L. Yin, J. H. Lee, Hepatoprotective role of Sestrin2 against chronic ER stress. Nat. Commun. 5, 4233 (2014).
30. F. Engin, A. Yermalovich, T. Nguyen, S. Hummasti, W. Fu, D. L. Eizirik, D. Mathis, G. S. Hotamisligil, Restoration of the unfolded protein response in pancreatic b cells protects mice against type 1 diabetes. Sci. Transl. Med. 5, 211ra156 (2013).
31. J. Y. Kim, K. J. Park, G. H. Kim, E. A. Jeong, D. Y. Lee, S. S. Lee, D. J. Kim, G. S. Roh, J. Song, S. H. Ki, W. H. Kim, In vivo activating transcription factor 3 silencing ameliorates the AMPK compensatory effects for ER stress-mediated β-cell dysfunction during the progression of type-2 diabetes. Cell. Signal. 25, 2348-2361 (2013).
32. M.Kars,L.Yang,M.F.Gregor,B.S.Mohammed,T.A.Pietka,B.N.Finck,B.W.Patterson, J.D.Horton,B.Mittendorfer,G.S.Hotamisligil,S.Klein,Tauroursodeoxycholicacidmay improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes 59, 1899-1905 (2010).
33. C. Xiao, A. Giacca, G. F. Lewis, Sodium phenylbutyrate, a drug with known capacity to reduce endoplasmic reticulum stress, partially alleviates lipid-induced insulin resistance and b-cell dysfunction in humans. Diabetes 60, 918-924 (2011).
34. C. Hetz, E. Chevet, H. P. Harding, Targeting the unfolded protein response in disease. Nat. Rev. Drug Discov. 12, 703-719 (2013).
35. C. Atkins, Q. Liu, E. Minthorn, S. Y. Zhang, D. J. Figueroa, K. Moss, T. B. Stanley, B. Sanders, A. Goetz, N. Gaul, A. E. Choudhry, H. Alsaid, B. M. Jucker, J. M. Axten, R. Kumar, Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 73, 1993-2002 (2013).
36. L.Wang,B.G.Perera,S.B.Hari,B.Bhhatarai,B.J.Backes,M.A.Seeliger,S.C.Schürer,S.A.Oakes, F. R. Papa, D. J. Maly, Divergent allosteric control of the IRE1a endoribonuclease using kinase inhibitors. Nat. Chem. Biol. 8, 982-989 (2012).
37. C. C. Hung, T. Ichimura, J. L. Stevens, J. V. Bonventre, Protection of renal epithelial cells against oxidative injury by endoplasmic reticulum stress preconditioning is mediated by ERK1/2 activation. J. Biol. Chem. 278, 29317-29326 (2003).
38. M. Peyrou, A. E. Cribb, Effect of endoplasmic reticulum stress preconditioning on cytotoxicity of clinically relevant nephrotoxins in renal cell lines. Toxicol. In Vitro 21, 878-886 (2007).
39. F. Usuki, M. Fujimura, A. Yamashita, Endoplasmic reticulum stress preconditioning attenuates methylmercury-induced cellular damage by inducing favorable stress responses. Sci. Rep. 3, 2346 (2013).
40. X. Liu, P. Garriga, H. G. Khorana, Structure and function in rhodopsin: Correct folding and misfolding in two point mutants in the intradiscal domain of rhodopsin identified in retinitis pigmentosa. Proc. Natl. Acad. Sci. U.S.A. 93, 4554-4559 (1996).
41. J. H. Lin, H. Li, D. Yasumura, H. R. Cohen, C. Zhang, B. Panning, K. M. Shokat, M. M. Lavail, P. Walter, IRE1 signaling affects cell fate during the unfolded protein response. Science 318, 944-949 (2007).
42. M. S. Gorbatyuk, T. Knox, M. M. LaVail, O. S. Gorbatyuk, S. M. Noorwez, W. W. Hauswirth, J. H. Lin, N. Muzyczka, A. S. Lewin, Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78. Proc. Natl. Acad. Sci. U.S.A. 107, 5961-5966 (2010).
43. M. Schröder, Endoplasmic reticulum stress responses. Cell. Mol. Life Sci. 65, 862-894 (2008).
44. D. Ai, J. M. Baez, H. Jiang, D. M. Conlon, A. Hernandez-Ono, M. Frank-Kamenetsky, S. Milstein, K. Fitzgerald, A. J. Murphy, C. W. Woo, A. Strong, H. N. Ginsberg, I. Tabas, D. J. Rader, A. R. Tall, Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice. J. Clin. Invest. 122, 1677-1687 (2012).
45. T. Mao, M. Shao, Y. Qiu, J. Huang, Y. Zhang, B. Song, Q. Wang, L. Jiang, Y. Liu, J. D. Han, P. Cao, J. Li, X. Gao, L. Rui, L. Qi, W. Li, Y. Liu, PKA phosphorylation couples hepatic inositol-requiring enzyme 1a to glucagon signaling in glucose metabolism. Proc. Natl. Acad. Sci. U.S.A. 108, 15852-15857 (2011).
46. A.Agouni,N.Mody,C.Owen,A.Czopek,D.Zimmer,M.Bentires-Alj,K.K.Bence,M.Delibegović, Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress. Biochem. J. 438, 369-378 (2011).
47. A. Bettaieb, N. Nagata, D. AbouBechara, S. Chahed, C. Morisseau, B. D. Hammock, F. G. Haj, Soluble epoxide hydrolase deficiency or inhibition attenuates diet-induced endoplasmic reticulum stress in liver and adipose tissue. J. Biol. Chem. 288, 14189-14199 (2013).
48. I. Cakir, N. E. Cyr, M. Perello, B. P. Litvinov, A. Romero, R. C. Stuart, E. A. Nillni, Obesity induces hypothalamic endoplasmic reticulum stress and impairs proopiomelanocortin (POMC) post-translational processing. J. Biol. Chem. 288, 17675-17688 (2013).
49. S. Jiang, C. Yan, Q. C. Fang, M. L. Shao, Y. L. Zhang, Y. Liu, Y. P. Deng, B. Shan, J. Q. Liu, H. T. Li, L. Yang, J. Zhou, Z. Dai, Y. Liu, W. P. Jia, Fibroblast growth factor 21 is regulated by the IRE1α- XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis. J. Biol. Chem. 289, 29751-29765 (2014).
50. N.K.Sharma,S.K.Das,A.K.Mondal,O.G.Hackney,W.S.Chu,P.A.Kern,N.Rasouli, H. J. Spencer, A. Yao-Borengasser, S. C. Elbein, Endoplasmic reticulum stress markers are associated with obesity in nondiabetic subjects. J. Clin. Endocrinol. Metab. 93,4532-4541 (2008).
51. M. F. Gregor, L. Yang, E. Fabbrini, B. S. Mohammed, J. C. Eagon, G. S. Hotamisligil, S. Klein, Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 58, 693-700 (2009).
52. D. R. Laybutt, A. M. Preston, M. C. Akerfeldt, J. G. Kench, A. K. Busch, A. V. Biankin, T. J. Biden, Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50, 752-763 (2007).
53. F. Engin, T. Nguyen, A. Yermalovich, G. S. Hotamisligil, Aberrant islet unfolded protein response in type 2 diabetes. Sci. Rep. 4, 4054 (2014).
54. S. Oyadomari, A. Koizumi, K. Takeda, T. Gotoh, S. Akira, E. Araki, M. Mori, Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J. Clin. Invest. 109, 525-532 (2002).
55. M. Latreille, M. K. Laberge, G. Bourret, L. Yamani, L. Larose, Deletion of Nck1 attenuates hepatic ER stress signaling and improves glucose tolerance and insulin signaling in liver of obese mice. Am. J. Physiol. Endocrinol. Metab. 300, E423-E434 (2011).
56. H.Nakagawa,A.Umemura,K.Taniguchi,J.Font-Burgada,D.Dhar,H.Ogata,Z.Zhong, M. A. Valasek, E. Seki, J. Hidalgo, K. Koike, R. J. Kaufman, M. Karin, ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26, 331-343 (2014).
57. S. J. Meex, M. M. van Greevenbroek, T. A. Ayoubi, R. Vlietinck, J. V. van Vliet-Ostaptchouk, M. H. Hofker, V. M. Vermeulen, C. G. Schalkwijk, E. J. Feskens, J. M. Boer, C. D. Stehouwer, C. J. van der Kallen, T. W. de Bruin, Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2 diabetes in Dutch Caucasians. J. Clin. Endocrinol. Metab. 92, 2720-2725 (2007).
58. H. Inoue, Y. Tanizawa, J. Wasson, P. Behn, K. Kalidas, E. Bernal-Mizrachi, M. Mueckler, H. Marshall, H. Donis-Keller, P. Crock, D. Rogers, M. Mikuni, H. Kumashiro, K. Higashi, G. Sobue, Y. Oka, M. A. Permutt, A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat. Genet. 20, 143-148 (1998).
59. R. E. Kaplon, E. Chung, L. Reese, K. Cox-York, D. R. Seals, C. L. Gentile, Activation of the unfolded protein response in vascular endothelial cells of nondiabetic obese adults. J. Clin. Endocrinol. Metab. 98, E1505-E1509 (2013).
60. R. Inagi, T. Kumagai, H. Nishi, T. Kawakami, T. Miyata, T. Fujita, M. Nangaku, Preconditioning with endoplasmic reticulum stress ameliorates mesangioproliferative glomerulonephritis. J. Am. Soc. Nephrol. 19, 915-922 (2008).
61. J. Li, J. J. Wang, S. X. Zhang, Preconditioning with endoplasmic reticulum stress mitigates retinal endothelial inflammation via activation of X-box binding protein 1. J. Biol. Chem. 286, 4912-4921 (2011).
62. F. Engin, G. S. Hotamisligil, Restoring endoplasmic reticulum function by chemical chaperones: An emerging therapeutic approach for metabolic diseases. Diabetes Obes. Metab. 12 Suppl. 2, 108-115 (2010).
63. W. J. Welch, C. R. Brown, Influence of molecular and chemical chaperones on protein folding. Cell Stress Chaperones 1, 109-115 (1996).
64. K. W. Jeong, J. M. Ku, M. W. Park, S. M. Park, J. E. Yang, T. G. Nam, Hydroxynaphthoic acids identified in a high throughput screening potently ameliorate endoplasmic reticulum stress as novel chemical chaperones. Chem. Pharm. Bull. 61, 740-746 (2013).
65. T. Gidalevitz, F. Stevens, Y. Argon, Orchestration of secretory protein folding by ER chaperones. Biochim. Biophys. Acta 1833, 2410-2424 (2013).
66. S. R. Brand, R. Kobayashi, M. B. Mathews, The Tat protein of human immunodeficiency virus type 1 is a substrate and inhibitor of the interferon-induced, virally activated protein kinase, PKR. J. Biol. Chem. 272, 8388-8395 (1997).
67. Y. Wang, G. Li, J. Goode, J. C. Paz, K. Ouyang, R. Screaton, W. H. Fischer, J. Chen, I. Tabas, M. Montminy, Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature 485,128-132 (2012).
68. A. P. Arruda, B. M. Pers, G. Parlakgül, E. Güney, K. Inouye, G. S. Hotamisligil, Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat. Med. 20, 1427-1435 (2014).
69. K. Eguchi, I. Manabe, Y. Oishi-Tanaka, M. Ohsugi, N. Kono, F. Ogata, N. Yagi, U. Ohto, M. Kimoto, K. Miyake, K. Tobe, H. Arai, T. Kadowaki, R. Nagai, Saturated fatty acid and TLR signaling link b cell dysfunction and islet inflammation. Cell Metab. 15, 518-533 (2012).
70. M. Furuhashi, G. Tuncman, C. Z. Görgün, L. Makowski, G. Atsumi, E. Vaillancourt, K. Kono, V. R. Babaev, S. Fazio, M. F. Linton, R. Sulsky, J. A. Robl, R. A. Parker, G. S. Hotamisligil, Downloaded from on June 19, 2015 Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447, 959-965 (2007).
71. 2+channel regulates energy balance and glucose metabolism. Am. J. Physiol. Endocrinol. Metab. 302, E807-E816 (2012).