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Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death
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.
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Autophagic responses to drugs may differ between transformed and nontransformed cells, between confluent and nonconfluent cells, or between cells grown with or without glucose.
“For example, autophagic responses to drugs may be different in transformed versus nontransformed cells, in confluent versus nonconfluent cells, or in cells grown with or without glucose [5].”
From Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1 (2021) · cites this paper as [5]
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Chaperone-mediated autophagy: selectivity pays off
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“The CMA-targeting motif is degenerate and allows a series of amino acid combinations (Cuervo, 2010), and, consistently, an analysis with relaxed stringency revealed that almost 79% of all statistically decreased proteins had potential a CMA targeting motif, including p53 and Hsc70, which have been previously reported…”
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Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894
Self-citationGuidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1
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Self-citationAutophagy in major human diseases
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Metadata
- Authors
- Xia, H.-G., Najafov, A., Geng, J., Galan-Acosta, L., Han, X., Guo, Y., Shan, B., Zhang, Y., Norberg, E., Zhang, T., Pan, L., Liu, J., Coloff, J. L., Ofengeim, D., Zhu, H., Wu, K., Cai, Y., Yates, J. R., Zhu, Z., Yuan, J., & Vakifahmetoglu-Norberg, H.
- Affiliations
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115 1
- Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden 2
- The Scripps Research Institute, Department of Chemical Physiology SR11, San Diego, CA 92121 3
- Interdisciplinary Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China 4
- Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China 5
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2015-08-31
- Volume
- 210
- Issue
- 5
- Pages
- 705-716
- ISSN
- 0021-9525
- 1540-8140
- PMC
- PMC4555813
- Cited by
- 122
- References
- 3
- Language
- en
- Update notices
- correction (2016-03-21)
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