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首页> 中文期刊> 《中国药理学与毒理学杂志》 >Isorhapontigenin(ISO) induces autophagy and cell growth inhibition by upregulation of SESN2/Sestrin2 in the Jun N-terminal kinase/AP-1 dependent mannerin human bladder cancer cells

Isorhapontigenin(ISO) induces autophagy and cell growth inhibition by upregulation of SESN2/Sestrin2 in the Jun N-terminal kinase/AP-1 dependent mannerin human bladder cancer cells

         
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OBJECTIVE To investigate the machenism that isorhapontigenin(ISO)induced autophagy and cell growth inhibition in human bladder cancer cells on the basis of the existing research results,for providing a new mechanistic insight into understanding the anti-cancer properties of ISO.METHODS Western blotting analysis was used to detect the expression of autophagypasswayproteins.Poly Jet transfection technology was used to establish transfected cell lines,and indirect immunofluorescence staining was applied to observe the punctuate dots of GFP-LC3.Anchorage-independent growth assaywas used to detect cell colony formation.RT-PCR was used to detect the m RNA levelof SESN2 after ISO treatment.The chromatin immunoprecipitation(CHIP)was used to detect the binding of transcription factor c-Jun and specificity SESN2 promoter sequence.RESULTS Our studies revealed that ISO-mediated autophagy induction occurred in a Sestrin2(SESN2)-dependent and Beclin 1(BECN1)-independent manner.Furthermore,we identified that ISO treatment induced SESN2 expression via a c-Jun N-terminal kinase(JNK)/c-Jun-dependent mechanism,in which ISO triggered JNK1-dependent c-Jun activation and facilitated the binding of c-Jun to consensus AP-1 binding site in the SESN2 promoter region,thereby led to a significant transcriptional induction of SESN2.Importantly,we found that SESN2 expression was dramatically down-regulated or even lost in human bladder cancer tissues as compared to their paired adjacent normal tissues,while ISO treatment was capable of elevating SESN2 expression effectively and inhibiting bladder cancer formation in BBN-induced mouse bladder tumors in vivo.CONCLUSION ISO treatment is able to induce autophagy and inhibit bladder cancer growth through JNK1/c-Jun dependent transcriptional induction of SESN2,which provides a novel mechanistic insight into understanding the inhibitory effect of ISO on bladder cancers and suggests that ISO might act as a promising preventive and/or therapeutic drug against human bladder cancer.

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