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

Daqian Xu, Xin-Jian Li, Fei Shao, Guishuai Lv, Hongwei Lv, Jong-Ho Lee, Xu Qian, Zheng Wang, Yan Xia, Linyong Du, Yanhua Zheng, Hongyang Wang, Jianxin Lyu, Zhimin Lu

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbereaav4570
JournalScience Advances
Volume5
Issue number4
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • General

MD Anderson CCSG core facilities

  • Functional Genomics Core

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