TY - JOUR
T1 - Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death
AU - Xia, Hong guang
AU - Najafov, Ayaz
AU - Geng, Jiefei
AU - Galan-Acosta, Lorena
AU - Han, Xuemei
AU - Guo, Yuan
AU - Shan, Bing
AU - Zhang, Yaoyang
AU - Norberg, Erik
AU - Zhang, Tao
AU - Pan, Lifeng
AU - Liu, Junli
AU - Coloff, Jonathan L.
AU - Ofengeim, Dimitry
AU - Zhu, Hong
AU - Wu, Kejia
AU - Cai, Yu
AU - Yates, John R.
AU - Zhu, Zhengjiang
AU - Yuan, Junying
AU - Vakifahmetoglu-Norberg, Helin
N1 - Publisher Copyright:
© 2015 Xia et al.
PY - 2015/8/31
Y1 - 2015/8/31
N2 - 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.
AB - 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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U2 - 10.1083/jcb.201503044
DO - 10.1083/jcb.201503044
M3 - Article
C2 - 26323688
AN - SCOPUS:84962177627
SN - 0021-9525
VL - 210
SP - 705
EP - 716
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 5
ER -