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

Hong guang Xia, Ayaz Najafov, Jiefei Geng, Lorena Galan-Acosta, Xuemei Han, Yuan Guo, Bing Shan, Yaoyang Zhang, Erik Norberg, Tao Zhang, Lifeng Pan, Junli Liu, Jonathan L. Coloff, Dimitry Ofengeim, Hong Zhu, Kejia Wu, Yu Cai, John R. Yates, Zhengjiang Zhu, Junying YuanHelin Vakifahmetoglu-Norberg

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)705-716
Number of pages12
JournalJournal of Cell Biology
Issue number5
StatePublished - Aug 31 2015
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology


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