The protein kinase activity of fructokinase A specifies the antioxidant responses of tumor cells by phosphorylating p62
Menée in vitro, à l'aide d'un modèle murin et de 90 échantillons tumoraux fixés au formaldéhyde et inclus en paraffine après prélèvement sur des patients atteints d'un carcinome hépatocellulaire, cette étude met en évidence un mécanisme par lequel la protéine kinase de la fructokinase A, en phosphorylant la protéine p62, favorise la carcinogenèse et la réponse des cellules cancéreuses au stress oxydant
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.