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J Cell Biol. 2015 Aug 31;210(5):705-16. doi: 10.1083/jcb.201503044.

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

Author information

1
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
2
Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
3
The Scripps Research Institute, Department of Chemical Physiology SR11, San Diego, CA 92121.
4
Interdisciplinary Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
5
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
6
Department of Cell Biology, Harvard Medical School, Boston, MA 02115 Interdisciplinary Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China jyuan@hms.harvard.edu.
7
Department of Cell Biology, Harvard Medical School, Boston, MA 02115 Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.

Abstract

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.

PMID:
26323688
PMCID:
PMC4555813
DOI:
10.1083/jcb.201503044
[Indexed for MEDLINE]
Free PMC Article

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