Metastatic melanoma cells rely on Sestrin2 to acquire anoikis resistance via detoxifying intracellular ROS

Abstract Distant metastases are responsible for the majority of melanoma mortalities. As a critical barrier against metastasis, anoikis is a distinct programmed cell death induced by the integrated stress from extracellular matrix (ECM) detachment. In order to survive, tumor cells employ various strategies for overcoming this barrier. Recently, Sestrin2(Sesn2) has been reported to play a protective role against integrated stress. In this study, we found ECM detachment triggered the up-regulation of Sesn2 in metastatic melanoma cells. Knockdown of Sesn2 impaired not only the cell viability but also the tumor sphere formation of melanoma cells in suspension cultures. Moreover, an elevated oxidative stress level was detected in Sesn2-silencing melanoma cells in suspension cultures, accompanied with an increased apoptosis rate. Last of all, in vivo studies indicated that Sesn2-knockdown remarkably reduced the formation of distant metastasis. Taken together, our findings illustrated that the up-regulation of Sesn2 in response to suspension stress plays a protective role in melanoma against anoikis by detoxifying oxidative stress.