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

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 IC50 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 as a novel mechanism to induce sorafenib primary resistance in HCC.

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

“…On the other hand, Sestrins may block oxidative damage-associated chemotherapy by reducing ROS (Budanov and Karin, 2008;Hagenbuchner et al, 2012). Sestrins were upregulated upon drug treatments in various type of pre-and mature-tumors as cell survival mechanism: head and neck cancers (Won et al, 2019), non-alcoholic steatohepatitis (Huang et al, 2020), HCC (Dai et al, 2018), osteosarcoma (Yen et al, 2018), acute pancreatitis (Norberg et al, 2018), colitis (Ro et al, 2016), bladder cancer (Hua et al, 2018), and prostate cancer (Fu et al, 2018;Shan et al, 2019). The distinctive roles of Sestrins as tumor suppressor or oncogene in the early or late stages of cancers need further investigation (Sanchez-Alvarez et al, 2019).…”

CC-223, NSC781406, and BGT226 Exerts a Cytotoxic Effect Against Pancreatic Cancer Cells via mTOR Signaling

“…Sestrins are induced by a variety of stresses such as DNA damage, hypoxia, and metabolic changes ( Dai et al, 2018 ). Previous studies have shown that most forms of cancer are associated with the down-regulation of Sestrin2 ( Chen et al, 2016 ; Seo et al, 2016 ).…”

Sestrins as a Therapeutic Bridge between ROS and Autophagy in Cancer

“…SESN3 can also be regulated by serum and cytokines/growth factors [55]. While information in this regard is still limited, a number of reports directly link dysregulated SESN expression levels with specific types of cancer cells [56,57,58], suggesting a potential for classifying and inferring oxidative stress resilience phenotypes.…”