title: Sestrin2 facilitates death receptor-induced apoptosis in lung adenocarcinoma cells through regulation of XIAP degradation.
abstract: 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.
authors: a Department of Human and Molecular Genetics ; Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University ; Richmond , VA USA.
authors: Boxiao
authors: B
authors: Ding
authors: a Department of Human and Molecular Genetics ; Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University ; Richmond , VA USA.
authors: Anita
authors: A
authors: Parmigiani
authors: b Department of Pharmacology and Toxicology ; Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University ; Richmond , VA USA.
authors: Chen
authors: C
authors: Yang
authors: a Department of Human and Molecular Genetics ; Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University ; Richmond , VA USA.
authors: Andrei V
authors: AV
authors: Budanov
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency / Q000502:physiology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D009687:Nuclear Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C465398:SESN2 protein, human; D000084622:Sestrins; C496866:XIAP protein, human
keywords: Sesn2, XIAP, death receptors, caspases, apoptosis