Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death.
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.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Hong-Guang
HG
Xia
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Ayaz
A
Najafov
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Jiefei
J
Geng
Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Lorena
L
Galan-Acosta
The Scripps Research Institute, Department of Chemical Physiology SR11, San Diego, CA 92121.
Xuemei
X
Han
Interdisciplinary Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Yuan
Y
Guo
Interdisciplinary Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Bing
B
Shan
Interdisciplinary Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Yaoyang
Y
Zhang
Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Erik
E
Norberg
Interdisciplinary Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Tao
T
Zhang
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Lifeng
L
Pan
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Junli
J
Liu
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Jonathan L
JL
Coloff
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Dimitry
D
Ofengeim
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Hong
H
Zhu
Interdisciplinary Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Kejia
K
Wu
Interdisciplinary Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Yu
Y
Cai
The Scripps Research Institute, Department of Chemical Physiology SR11, San Diego, CA 92121.
John R
JR
Yates
Interdisciplinary Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Zhengjiang
Z
Zhu
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.
Junying
J
Yuan
Department of Cell Biology, Harvard Medical School, Boston, MA 02115 Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Helin
H
Vakifahmetoglu-Norberg
D001343:Autophagy / Q000502:physiology*; D052160:Benzothiazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology* / Q000473:pathology*; D008247:Lysosomes / Q000473:pathology; D018832:Molecular Chaperones / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D059748:Proteolysis; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D052160:Benzothiazoles; D018832:Molecular Chaperones; D010671:Phenylurea Compounds; C544967:quizartinib; D006593:Hexokinase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D005947:Glucose