Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death.
Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death.
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DOI：
10.1083/jcb.201503044
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发表时间：
2015-08-31
期刊：
影响因子：
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通讯作者：
Vakifahmetoglu-Norberg H
中科院分区：
文献类型：
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作者：
Xia HG;Najafov A;Geng J;Galan-Acosta L;Han X;Guo Y;Shan B;Zhang Y;Norberg E;Zhang T;Pan L;Liu J;Coloff JL;Ofengeim D;Zhu H;Wu K;Cai Y;Yates JR;Zhu Z;Yuan J;Vakifahmetoglu-Norberg H
受体酪氨酸激酶Flt3的微扰引起的代谢应激使癌细胞对自噬抑制敏感，并导致伴侣介导的自噬过度激活，从而通过HK2的降解在癌细胞中引发代谢灾难。己糖激酶II(HK2)是参与葡萄糖代谢的关键酶，受生长因子信号调节，在肿瘤的发生和维持中起重要作用。在这里，我们表明，在非急性髓系白血病细胞中，由受体酪氨酸激酶Flt3的扰动引发的代谢应激使癌细胞对自噬抑制敏感，并导致伴侣介导的自噬(CMA)的过度激活。我们的研究结果表明，Flt3是细胞营养状态的重要感受器，并阐明了CMA在代谢调节和介导癌细胞死亡中的作用和分子机制。重要的是，我们的蛋白质组分析表明HK2是CMA底物，CMA对HK2的降解受葡萄糖供应的调节。我们揭示了一种新的机制，通过抑制Flt3和自噬，CMA的过度激活可能被药理学地利用来消除癌细胞。我们的研究描绘了一种新的药理策略来促进HK2在癌细胞中的降解。
Metabolic stress caused by perturbation of receptor tyrosine kinase FLT3 sensitizes cancer cells to autophagy inhibition and leads to excessive activation of chaperone-mediated autophagy, which triggers metabolic catastrophe in cancer cells through the degradation of HK2. Hexokinase II (HK2), a key enzyme involved in glucose metabolism, is regulated by growth factor signaling and is required for initiation and maintenance of tumors. Here we show that metabolic stress triggered by perturbation of receptor tyrosine kinase FLT3 in non–acute myeloid leukemia cells sensitizes cancer cells to autophagy inhibition and leads to excessive activation of chaperone-mediated autophagy (CMA). Our data demonstrate that FLT3 is an important sensor of cellular nutritional state and elucidate the role and molecular mechanism of CMA in metabolic regulation and mediating cancer cell death. Importantly, our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability. We reveal a new mechanism by which excessive activation of CMA may be exploited pharmacologically to eliminate cancer cells by inhibiting both FLT3 and autophagy. Our study delineates a novel pharmacological strategy to promote the degradation of HK2 in cancer cells.