Akt-dependent glucose metabolism promotes Mcl-1 synthesis to maintain cell survival and resistance to Bcl-2 inhibition.
Akt-dependent glucose metabolism promotes Mcl-1 synthesis to maintain cell survival and resistance to Bcl-2 inhibition.
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DOI：
10.1158/0008-5472.can-10-4531
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发表时间：
2011-08-01
期刊：
影响因子：
11.2
通讯作者：
Rathmell JC
中科院分区：
文献类型：
--
作者：
Coloff JL;Macintyre AN;Nichols AG;Liu T;Gallo CA;Plas DR;Rathmell JC
大多数癌细胞利用有氧糖酵解，而磷脂酰肌醇3-激酶(PI3K)/Akt/mTOR通路的激活可以促进这一代谢程序，使细胞对葡萄糖依赖。虽然操纵葡萄糖代谢可能提供了一种特异性消除癌细胞的方法，但细胞代谢和细胞凋亡之间的机制联系仍然知之甚少。在这里，我们研究了抗凋亡的Bcl-2家族蛋白Mcl-1在抑制Akt诱导的有氧糖酵解后细胞死亡中的作用和代谢调节。在充足的葡萄糖存在下，激活的Akt可阻止Mcl-1表达的丢失，并保护细胞免受生长因子剥夺诱导的细胞凋亡。MCL-1结合并抑制促凋亡的Bcl-2家族蛋白Bim，促进细胞存活。然而，抑制糖代谢导致BIM的诱导，Mcl-1的表达减少，并导致细胞凋亡。促凋亡的Bcl2/Bclxl/Bclw抑制剂ABT-737显示出临床应用前景，但Mcl-1上调可促进耐药。重要的是，在弥漫性大B细胞白血病细胞中，葡萄糖代谢或mTORC1的抑制克服了Mcl-1介导的耐药性。综上所述，这些数据表明Mcl-1蛋白的合成受到代谢的严格控制，控制葡萄糖代谢可能提供一种机制来抑制Mcl-1的表达，并使癌细胞对凋亡敏感。
Most cancer cells utilize aerobic glycolysis, and activation of the phosphatidyl-inositol 3-kinase (PI3K)/Akt/mTOR pathway can promote this metabolic program to render cells glucose-dependent. While manipulation of glucose metabolism may provide a means to specifically eliminate cancer cells, mechanistic links between cell metabolism and apoptosis remain poorly understood. Here we examine the role and metabolic regulation of the anti-apoptotic Bcl-2 family protein Mcl-1 in cell death upon inhibition of Akt-induced aerobic glycolysis. In the presence of adequate glucose, activated Akt prevented the loss of Mcl-1 expression and protected cells from growth factor-deprivation induced apoptosis. Mcl-1 associated with and inhibited the pro-apoptotic Bcl-2 family protein Bim, contributing to cell survival. However, suppression of glucose metabolism led to induction of Bim, decreased expression of Mcl-1, and apoptosis. The pro-apoptotic Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, shows clinical promise, but Mcl-1 upregulation can promote resistance. Importantly, inhibition of glucose metabolism or mTORC1 overcame Mcl-1-mediated resistance in diffuse large B cell leukemic cells. Together these data show that Mcl-1 protein synthesis is tightly controlled by metabolism and that manipulation of glucose metabolism may provide a mechanism to suppress Mcl-1 expression and sensitize cancer cells to apoptosis.