Apoptosis plays a critical physiological role in controlling cell number and eliminating damaged, non-functional and transformed cells. Cancerous cells as well as some types of normal cells are often resistant to cell death induced by pro-inflammatory cytokines through death receptors. This potentially allows cancer cells to evade the control from the immune system and to proceed toward a more malignant stage, although the mechanisms of this evasion are not well established. We have recently identified the stress-responsive Sestrin2 protein as a critical regulator of cell viability under stress conditions. Sestrin2 is a member of a small family of antioxidant proteins and inhibitors of mechanistic Target of Rapamycin Complex 1 (mTORC1) kinase. Down-regulation of Sestrin1/2 leads to genetic instability and accelerates the growth of lung adenocarcinoma xenografts. Here we addressed the potential role of Sestrin2 in regulation of cell death induced by TNFR1 and related Fas and TRAIL receptors in lung adenocarcinoma cells. We found that Sestrin2 silencing strongly inhibits cytokine-induced cell death through a mechanism independent of ROS and mTORC1 regulation. We determined that the X-linked inhibitor of apoptosis protein (XIAP) plays a critical role in the control of cytokine-induced cell death by Sestrin2. Thus our study defines a new, previously unrecognized role of Sestrin2 in the regulation of apoptosis.
Keywords: Sesn2, XIAP, death receptors, caspases, apoptosis.