Metastatic Melanoma Cells Rely on Sestrin2 to Acquire Anoikis Resistance via Detoxifying Intracellular ROS

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, Sesn2 has been reported to play a protective role against integrated stress. In this study, we found that ECM detachment triggered the upregulation of Sesn2 in metastatic melanoma cells. The 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. Finally, in vivo studies indicated that the Sesn2-knockdown reduced the formation of distant metastasis remarkably. Taken together, our findings illustrated that the upregulation of Sesn2 in response to suspension stress plays a protective role in melanoma against anoikis by detoxifying oxidative stress.