Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2).
Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2).
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DOI：
10.1007/s00125-012-2475-7
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发表时间：
2012-05
期刊：
影响因子：
8.2
通讯作者：
Herbert, T. P.
中科院分区：
文献类型：
--
作者：
Barlow, A. D.;Xie, J.;Moore, C. E.;Campbell, S. C.;Shaw, J. A. M.;Nicholson, M. L.;Herbert, T. P.
Rapamycin (sirolimus) is one of the primary immunosuppressants for islet transplantation. Yet there is evidence that the long-term treatment of islet-transplant patients with rapamycin may be responsible for subsequent loss of islet graft function and viability. Therefore, the primary objective of this study was to elucidate the molecular mechanism of rapamycin toxicity in beta cells. Experiments were performed on isolated rat and human islets of Langerhans and MIN6 cells. The effects of rapamycin and the roles of mammalian target of rapamycin complex 2 (mTORC2)/protein kinase B (PKB) on beta cell signalling, function and viability were investigated using cell viability assays, insulin ELISA assays, kinase assays, western blotting, pharmacological inhibitors, small interfering (si)RNA and through the overproduction of a constitutively active mutant of PKB. Rapamycin treatment of MIN6 cells and islets of Langerhans resulted in a loss of cell function and viability. Although rapamycin acutely inhibited mTOR complex 1 (mTORC1), the toxic effects of rapamycin were more closely correlated to the dissociation and inactivation of mTORC2 and the inhibition of PKB. Indeed, the overproduction of constitutively active PKB protected islets from rapamycin toxicity whereas the inhibition of PKB led to a loss of cell viability. Moreover, the selective inactivation of mTORC2 using siRNA directed towards rapamycin-insensitive companion of target of rapamycin (RICTOR), mimicked the toxic effects of chronic rapamycin treatment. This report provides evidence that rapamycin toxicity is mediated by the inactivation of mTORC2 and the inhibition of PKB and thus reveals the molecular basis of rapamycin toxicity and the essential role of mTORC2 in maintaining beta cell function and survival. The online version of this article (doi:10.1007/s00125-012-2475-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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影响因子：
4.1
作者：
Gomez, Edith;Powell, Mike L.;Herbert, Terence P.
通讯作者：
Herbert, Terence P.
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影响因子：
7.7
作者：
Elghazi L;Balcazar N;Blandino-Rosano M;Cras-Méneur C;Fatrai S;Gould AP;Chi MM;Moley KH;Bernal-Mizrachi E
通讯作者：
Bernal-Mizrachi E
影响因子：
10.9
作者：
Elghazi, Lynda;Bernal-Mizrachi, Ernesto
通讯作者：
Bernal-Mizrachi, Ernesto
影响因子：
6
作者：
Favaro, Enrica;Miceli, Ilaria;Zanone, Maria M.
通讯作者：
Zanone, Maria M.
影响因子：
5.6
作者：
Moore, Claire E. J.;Xie, Jianling;Herbert, Terence P.
通讯作者：
Herbert, Terence P.