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标题：Synthetic lethality of combined glutaminase and Hsp90 inhibition in mTORC1-driven tumor cells
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作者：Jing Li ; Alfredo Csibi ; Sun Yang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：E21-E29
DOI：10.1073/pnas.1417015112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe mammalian target of rapamycin complex 1 (mTORC1)-mediated signaling regulates protein translation, cell size/growth, cell survival, and metabolism. This signaling is commonly deregulated in cancer as well as genetic disorders such as tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. Recent studies have shown that the mTORC1 inhibitor rapamycin and its analogs generally decrease proliferation rather than inducing cell death. In this study, we found a strategy that rapidly triggers death of cells with activated mTORC1-mediated signaling by using the combination of aminohydrolase enyzme glutaminase and chaperone protein heat shock protein 90 inhibitors. We believe this combination strategy may have potential to be developed into therapeutic use for the treatment of mTORC1-driven tumors. The mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals from growth factors, nutrients, and cellular energy status to control a wide range of metabolic processes, including mRNA biogenesis; protein, nucleotide, and lipid synthesis; and autophagy. Deregulation of the mTORC1 pathway is found in cancer as well as genetic disorders such as tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis. Recent studies have shown that the mTORC1 inhibitor rapamycin and its analogs generally suppress proliferation rather than induce apoptosis. Therefore, it is critical to use alternative strategies to induce death of cells with activated mTORC1. In this study, a small-molecule screen has revealed that the combination of glutaminase (GLS) and heat shock protein 90 (Hsp90) inhibitors selectively triggers death of TSC2-deficient cells. At a mechanistic level, high mTORC1-driven translation rates in TSC1/2-deficient cells, unlike wild-type cells, sensitizes these cells to endoplasmic reticulum (ER) stress. Thus, Hsp90 inhibition drives accumulation of unfolded protein and ER stress. When combining proteotoxic stress with oxidative stress by depletion of the intracellular antioxidant glutathione by GLS inhibition, acute cell death is observed in cells with activated mTORC1 signaling. This study suggests that this combination strategy may have the potential to be developed into a therapeutic use for the treatment of mTORC1-driven tumors.
关键词：glutaminase ; Hsp90 ; mTORC1 ; synthetic lethality ; inhibitors