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.