title: SESN2/sestrin 2 induction-mediated autophagy and inhibitory effect of isorhapontigenin (ISO) on human bladder cancers.
abstract: Isorhapontigenin (ISO) is a new derivative of stilbene isolated from the Chinese herb Gnetum cleistostachyum. Our recent studies have revealed that ISO treatment at doses ranging from 20 to 80 μM triggers apoptosis in multiple human cancer cell lines. In the present study, we evaluated the potential effect of ISO on autophagy induction. We found that ISO treatment at sublethal doses induced autophagy effectively in human bladder cancer cells, which contributed to the inhibition of anchorage-independent growth of cancer cells. In addition, our studies revealed that ISO-mediated autophagy induction occurred in a SESN2 (sestrin 2)-dependent and BECN1 (Beclin 1, autophagy related)-independent manner. Furthermore, we identified that ISO treatment induced SESN2 expression via a MAPK8/JNK1 (mitogen-activated protein kinase 8)/JUN-dependent mechanism, in which ISO triggered MAPK8-dependent JUN activation and facilitated the binding of JUN to a 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 downregulated or even lost in human bladder cancer tissues as compared to their paired adjacent normal tissues. Collectively, our results demonstrate that ISO treatment induces autophagy and inhibits bladder cancer growth through MAPK8-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.
authors.affiliation: a Department of Clinical Pharmacology , Affiliated Hospital, Academy of Military Medical Sciences , Beijing , China.|b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY USA.
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Liang
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY USA.
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhu
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY USA.|c Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.
authors.forename: Haishan
authors.initials: H
authors.lastname: Huang
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY USA.
authors.forename: Daimin
authors.initials: D
authors.lastname: Xiang
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY USA.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY USA.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY USA.
authors.forename: Yulei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY USA.
authors.forename: Honglei
authors.initials: H
authors.lastname: Jin
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY USA.
authors.forename: Guosong
authors.initials: G
authors.lastname: Jiang
authors.affiliation: a Department of Clinical Pharmacology , Affiliated Hospital, Academy of Military Medical Sciences , Beijing , China.
authors.forename: Zeyuan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY USA.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015195:Drug Design; D004365:Drugs, Chinese Herbal; D015972:Gene Expression Regulation, Neoplastic; D035684:Gnetum / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010936:Plant Extracts / Q000737:chemistry; D011401:Promoter Regions, Genetic; D013267:Stilbenes / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D000084622:Sestrins
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D004365:Drugs, Chinese Herbal; D048055:Mitogen-Activated Protein Kinase 8; D009687:Nuclear Proteins; D010936:Plant Extracts; D013267:Stilbenes; D018808:Transcription Factor AP-1; C491997:BECN1 protein, human; C465398:SESN2 protein, human; D000084622:Sestrins; C432307:isorhapontigenin
keywords: MAPK8; autophagy; bladder cancer; isorhapontigenin; sestrin 2