CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis.
Hepatocellular carcinoma (HCC) is one of the most deadly cancers that still lacks effective treatments. Dysregulation of kinase signaling has frequently been reported to contribute to HCC. In this study, we used bioinformatic approaches to identify kinases that regulate gene expression changes in human HCCs and two murine HCC models. We identified a role for calcium/calmodulin-dependent protein kinases II gamma isoform (CAMK2γ) in hepatocarcinogenesis. CAMK2γ-/-mice displayed severely enhanced chemical-induced hepatocarcinogenesis compared with wild-type controls. Mechanistically, CAMK2γ deletion potentiates hepatic activation of mechanistic target of rapamycin complex 1 (mTORC1), which results in hyperproliferation of hepatocytes. Inhibition of mTORC1 by rapamycin effectively attenuates the compensatory proliferation of hepatocytes in CAMK2γ-/-livers. We further demonstrated that CAMK2γ suppressed growth factor- or insulin-induced mTORC1 activation by inhibiting IRS1/AKT signaling. Taken together, our results reveal a novel mechanism by which CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis.
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.
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Meng
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.|Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
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Ma
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.|Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
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Du
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.
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Wang
School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.
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M
He
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.|Department of Hematology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Zhejiang University, Hangzhou, Zhejiang, China.
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Gu
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.|Cancer Institute, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
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Zhang
Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
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Han
Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
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Z
Fang
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.
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Gan
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.
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Van Ness
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.|State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
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X
Fu
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.|Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
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DE
Schones
Department of Hematology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Zhejiang University, Hangzhou, Zhejiang, China.|Cancer Institute, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
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Xu
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.|Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
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Huang
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000139:chemically induced; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine / Q000494:pharmacology; D017353:Gene Deletion; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D046912:Multiprotein Complexes; D004052:Diethylnitrosamine; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C517662:CAMK2G protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2