Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma

作者：Jimin Dai, Jimin Dai, Qichao Huang, Kunwei Niu, Bo Wang, Yijie Li, Chen Dai, Zhi‐Nan Chen, Kaishan Tao, Jingyao Dai, Jingyao Dai · 发表于：Cancer Medicine · 年份：2018 · DOI：10.1002/cam4.1826 · 被引用次数：50 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Endoplasmic Reticulum Stress and Disease、Hepatocellular Carcinoma Treatment and Prognosis

Abstract Hepatocellular carcinoma (HCC) is the malignancy derived from normal hepatocytes with increasing incidence and extremely poor prognosis worldwide. The only approved first‐line systematic treatment agent for HCC, sorafenib, is capable to effectively improve advanced HCC patients’ survival. However, it is gradually recognized that the therapeutic response to sorafenib could be drastically diminished after short‐term treatment, defined as primary resistance. The present study is aimed to explore the role of stress‐inducible protein Sestrin2 (SESN2), one of the most important sestrins family members, in sorafenib primary resistance. Herein, we initially found that SESN2 expression was significantly up‐regulated in both HCC cell lines and tissues compared to normal human hepatocytes and corresponding adjacent liver tissues, respectively. In addition, SESN2 expression was highly correlated with sorafenib IC 50 of HCC cell lines. Thereafter, we showed that sorafenib treatment resulted in an increase of SESN2 expression and the knockdown of SESN2 exacerbated sorafenib‐induced proliferation inhibition and cell apoptosis. Further mechanistic study uncovered that SESN2 deficiency impaired both AKT and AMPK phosphorylation and activation after sorafenib treatment. Moreover, the correlations between SESN2 expression and both phosphor‐AKT and phosphor‐AMPK expression were illustrated in HCC tissues. Taken together, our study demonstrates that SESN2 activates AKT and AMPK signaling...