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Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK

文献类型：期刊论文

作者Elksnis, Andris1; Schiffer, Tomas A.1; Palm, Fredrik1; Wang, Yun1; Cen, Jing1; Turpaev, Kyril1,2; Ngamjariyawat, Anongnad1; Younis, Shady3,4; Huang, Suling5; Shen, Yu5
刊名CLINICAL SCIENCE
出版日期2021-10-01
卷号135期号:19页码:2243-2263
ISSN号0143-5221
DOI10.1042/CS20210604
通讯作者Welsh, Nils(nils.welsh@mcb.uu.se) ; Wang, Xuan(xuan.wang@mcb.uu.se)
英文摘要The protein tyrosine kinase inhibitor imatinib is used in the treatment of various malignancies but may also promote beneficial effects in the treatment of diabetes. The aim of the present investigation was to characterize the mechanisms by which imatinib protects insulin producing cells. Treatment of non-obese diabetic (NOD) mice with imatinib resulted in increased beta-cell AMP-activated kinase (AMPK) phosphorylation. Imatinib activated AMPK also in vitro, resulting in decreased ribosomal protein S6 phosphorylation and protection against islet amyloid polypeptide (IAPP)-aggregation, thioredoxin interacting protein (TXNIP) up-regulation and beta-cell death. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) mimicked and compound C counteracted the effect of imatinib on beta-cell survival. Imatinib-induced AMPK activation was preceded by reduced glucose/pyruvate-dependent respiration, increased glycolysis rates, and a lowered ATP/AMP ratio. Imatinib augmented the fractional oxidation of fatty acids/malate, possibly via a direct interaction with the beta-oxidation enzyme enoyl coenzyme A hydratase, short chain, 1, mitochondrial (ECHS1). In non-beta cells, imatinib reduced respiratory chain complex I and II-mediated respiration and acyl-CoA carboxylase (ACC) phosphorylation, suggesting that mitochondrial effects of imatinib are not beta-cell specific. In conclusion, tyrosine kinase inhibitors modestly inhibit mitochondrial respiration, leading to AMPK activation and TXNIP down-regulation, which in turn protects against beta-cell death.
WOS关键词TYROSINE KINASE INHIBITORS ; MESYLATE ; GLUCOSE ; METABOLISM ; PHOSPHORYLATION ; EXTRACTION ; MECHANISM ; APOPTOSIS ; AUTOPHAGY ; SAMPLES
资助项目Diabetesforbundet[DIA 2020-540] ; family Ernfors Fund ; Barndiabetesfonden ; EXODIAB
WOS研究方向Research & Experimental Medicine
语种英语
出版者PORTLAND PRESS LTD
WOS记录号WOS:000707198700002
源URL[http://119.78.100.183/handle/2S10ELR8/298421]  
专题新药研究国家重点实验室
通讯作者Welsh, Nils; Wang, Xuan
作者单位1.Uppsala Univ, Dept Med Cell Biol, Sci Life Lab, Box 571, SE-75123 Uppsala, Sweden
2.Russian Acad Sci, Ctr Theoret Problems Physicochem Pharmacol, Moscow, Russia
3.Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, Uppsala, Sweden
4.Stanford Univ, Div Immunol & Rheumatol, Stanford, CA 94305 USA
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
6.KBC Byggnaden, Swedish Metabol Ctr, Plan 3,Linnaeus Vag 6, S-90187 Umea, Sweden
推荐引用方式
GB/T 7714		 Elksnis, Andris,Schiffer, Tomas A.,Palm, Fredrik,et al. Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK[J]. CLINICAL SCIENCE,2021,135(19):2243-2263.
APA Elksnis, Andris.,Schiffer, Tomas A..,Palm, Fredrik.,Wang, Yun.,Cen, Jing.,...&Wang, Xuan.(2021).Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK.CLINICAL SCIENCE,135(19),2243-2263.
MLA Elksnis, Andris,et al."Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK".CLINICAL SCIENCE 135.19(2021):2243-2263.

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来源：上海药物研究所

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