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

The Journal of Cell Biology
Hong-Guang XiaHelin Vakifahmetoglu-Norberg

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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Citations

Jun 14, 2016·Vascular Pharmacology·Melanie Uebelhoer, M Luisa Iruela-Arispe
Feb 9, 2016·The FEBS Journal·Inmaculada Tasset, Ana Maria Cuervo
Aug 4, 2016·Ageing Research Reviews·Maria Xilouri, Leonidas Stefanis
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Dec 13, 2016·Biochemical and Biophysical Research Communications·Junya SuzukiNobuyuki Tanaka
Feb 19, 2017·Biochemical and Biophysical Research Communications·Helin Vakifahmetoglu-NorbergErik Norberg
Dec 17, 2017·The Journal of Biological Chemistry·Kumsal Tekirdag, Ana Maria Cuervo
Apr 8, 2018·Nature Reviews. Molecular Cell Biology·Susmita Kaushik, Ana Maria Cuervo
Dec 14, 2017·Essays in Biochemistry·Steve CatarinoHenrique Girão
Jun 23, 2018·Autophagy·Laury LescatIban Seiliez
Oct 11, 2017·Molecular and Cellular Biology·Matilda ErikssonHelin Vakifahmetoglu-Norberg
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Dec 13, 2018·Physiological Reviews·Åsa B Gustafsson, Gerald W Dorn
Jan 28, 2018·Cell Death & Disease·Amanda Tomie OuchidaJunying Yuan
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Jan 4, 2021·Molecular and Cellular Biochemistry·Zhaozhong LiaoNing Li
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Feb 21, 2021·Experimental Eye Research·Jianhui XiaoDavid N Zacks
Mar 7, 2021·International Journal of Molecular Sciences·Alessia Lo DicoLuisa Ottobrini

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Methods Mentioned

BETA
transfection
coimmunoprecipitation
Assay

Software Mentioned

Integrated Proteomics Pipeline - IP2
BASALT
QuikChange Primer Design
ArrayScan HCS
ProLuCID
MotifGen
DTASelect2
Xcalibur

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