Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death

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.

In:The Journal of cell biology: Rockefeller University Press210:5, s. 705-7161540-81400021-9525

By the author/editor: Xia, HG; Najafov, A; Geng, JF; Galan-Acosta, L; Han, XM; Guo, Y; show more...; Shan, B; Zhang, YY; Norberg, E; Zhang, T; Pan, LF; Liu, JL; Coloff, JL; Ofengeim, D; Zhu, H; Wu, KJ; Cai, Y; Yates, JR; Zhu, ZJ; Yuan, JY; Vakifahmetoglu-N ...; show less...

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