title: Upregulation of sestrin 2 expression via JNK pathway activation contributes to autophagy induction in cancer cells.
abstract: JNK signaling functions to induce defense mechanisms that protect organisms against a variety of different situations. The sestrin 2 gene, a p53-regulated member of the sestrins family, which lead to AMPK-dependent inhibition of TOR signaling, emerges as a novel player in autophagy induction. However, the relationship between JNK pathway, autophagy induction and sestrin 2 expression remains elusive. In the present study, we identify JNK as a regulator of autophagy in nasopharyngeal carcinoma cell lines CNE1 and CNE2 exposed to excisanin A or serum deprivation and demonstrate that activation of JNK can cause upregulation of sestrin 2 expression, which could be blocked by specific siRNAs directed against JNK1/2 or c-Jun. Chromatin immunoprecipitation and luciferase reporter analysis revealed that c-Jun was transcriptionally involved in the regulation of sestrin 2. Furthermore, knockdown of sestrin 2 by siRNAs similarly inhibited autophagy induction. Moreover, silencing the expression of autophagy related gene ATG5 or sestrin 2 significantly decreases cell death induced by excisanin A. Our results therefore identify JNK as a novel mediator of sestrin 2 expression, which plays a key role in autophagy induction following anticancer therapies in cancers.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiao-Yue
authors.initials: XY
authors.lastname: Zhang
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Wu
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
authors.forename: Ting
authors.initials: T
authors.lastname: Sun
authors.forename: Gong-Kan
authors.initials: GK
authors.lastname: Feng
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhu
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004224:Diterpenes / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000084622:Sestrins
chemical_list: D000071187:Autophagy-Related Protein 5; D004224:Diterpenes; D048031:JNK Mitogen-Activated Protein Kinases; D008869:Microtubule-Associated Proteins; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; C502778:ATG5 protein, human; C465398:SESN2 protein, human; D000084622:Sestrins; C047381:excisanin A