Dihydroartemisinin exerts antitumour activity by blocking SIRT2-IGFBP1-induced PI3K/AKT/mTOR signal transduction in liver cancer

Abstract

Abstract The human NAD (+)-dependent deacetylase silent information regulator isoform 2 (SIRT2) is the cytoplasm-localized member of the sirtuin family, which has received increasing attention for its potential roles in cancer diagnosis and therapy. However, its role is still under debate, and its molecular mechanism remains unclarified. In this study, we thoroughly investigated the function and regulatory mechanism of SIRT2 in the tumorigenesis of liver cancer and found that SIRT2 is highly expressed in liver cancer tissues and is distributed mainly in the cytoplasm of liver cancer cells. The SIRT2 expression level is positively related to cell proliferation in vitro and tumour growth in vivo. We found that SIRT2 can upregulate IGFBP1 expression and subsequently activate the PI3K/AKT/mTOR signalling pathway and that IGFBP1 is essential for the tumour-promoting function of SIRT2 in liver cancer. Moreover, we characterized that dihydroartemisinin, one of the main active metabolites of artemisinin derivatives can inhibit liver cancer cell proliferation and liver tumour growth by promoting ubiquitin-dependent SIRT2 degradation and subsequently blocking SIRT2-IGFBP1-induced PI3K/AKT/mTOR signal pathway.