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Sci Adv. 2019 Apr 24;5(4):eaav4570. doi: 10.1126/sciadv.aav4570. eCollection 2019 Apr.

The protein kinase activity of fructokinase A specifies the antioxidant responses of tumor cells by phosphorylating p62.

Xu D1,2, Li X1, Shao F3,4,5, Lv G6,7, Lv H6,7, Lee JH1, Qian X8, Wang Z9, Xia Y1, Du L10, Zheng Y1, Wang H6,7,11, Lyu J10,12, Lu Z1,13.

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Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266061, China.
Qingdao Cancer Institute, Qingdao, Shandong 266061, China.
State Key Laboratory of Molecular Oncology, Department of Thoracic Surgery, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
National Center for Liver Cancer, Shanghai 201805, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu 211166, China.
Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA.
Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China.
Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhengjiang University School of Medicine, Hangzhou 310029, China.


Cancer cells often encounter oxidative stress. However, it is unclear whether normal and cancer cells differentially respond to oxidative stress. Here, we demonstrated that under oxidative stress, hepatocellular carcinoma (HCC) cells exhibit increased antioxidative response and survival rates compared to normal hepatocytes. Oxidative stimulation induces HCC-specifically expressed fructokinase A (KHK-A) phosphorylation at S80 by 5'-adenosine monophosphate-activated protein kinase. KHK-A in turn acts as a protein kinase to phosphorylate p62 at S28, thereby blocking p62 ubiquitination and enhancing p62's aggregation with Keap1 and Nrf2 activation. Activated Nrf2 promotes expression of genes involved in reactive oxygen species reduction, cell survival, and HCC development in mice. In addition, phosphorylation of KHK-A S80 and p62 S28 and nuclear accumulation of Nrf2 are positively correlated in human HCC specimens and with poor prognosis of patients with HCC. These findings underscore the role of the protein kinase activity of KHK-A in antioxidative stress and HCC development.

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