title: Curcumin promotes apoptosis by activating the p53-miR-192-5p/215-XIAP pathway in non-small cell lung cancer.
abstract: Curcumin has attracted increasing interest as an anti-cancer drug for decades. The mechanisms of action involve multiple cancer-related signaling pathways. Recent studies highlighted curcumin has epigenetic regulatory effects on miRNA in cancers. In the present study, we demonstrated the proapoptotic effects of curcumin in vitro and in vivo. miRNA microarray and qPCR indicated that miR-192-5p and miR-215 were the most responsive miRNAs upon curcumin treatment in H460 and A427 cells. Functional studies showed miR-192-5p/215 were putative tumor suppressors in non-small cell lung cancer. Curcumin also promoted miR-192-5p/215 expressions in A549 cells (p53 wild type) but not in H1299 cells (p53-null). Conditional knockdown of p53 by tetracycline inducible expression system significantly abrogated curcumin-induced miR-192-5p/215 upregulation in the p53 wild-type H460, A427 and A549 cells. Conversely, ectopic expression of exogenous wild-type but not R273H mutant p53 in the p53-null H1299 cells enabled miR-192-5p/215 response to curcumin treatment. The proapoptotic effects of curcumin also depended on miR-192-5p/215 induction, and antagonizing miR-192-5p/215 expression attenuated curcumin-induced apoptosis in H460, A427 and A549 cells, but not in H1299 cells. Finally, X-linked inhibitor of apoptosis (XIAP) is proved to be a novel transcriptional target of miR-192-5p/215. Taken together, this study highlights that the proapoptotic effects of curcumin depend on miR-192-5p/215 induction and the p53-miR-192-5p/215-XIAP pathway is an important therapeutic target for non-small cell lung cancer.
authors.affiliation: Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China; State Key Laboratory of Cancer Biology (CBSKL), Fourth Military Medical University, Xi'an, China.
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Ye
authors.affiliation: Department of Hand Surgery, 401 Hospital, Qingdao, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China; State Key Laboratory of Cancer Biology (CBSKL), Fourth Military Medical University, Xi'an, China.
authors.forename: Jiän
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, School of Pharmacy, Fourth Military Medical University, Xi'an, China; Deparment of Pharmacy, 401 Hospital, Qingdao, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Miao
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China; State Key Laboratory of Cancer Biology (CBSKL), Fourth Military Medical University, Xi'an, China. Electronic address: bioyao@fmmu.edu.cn.
authors.forename: Libo
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: zhangjian197011@gmail.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: C546783:MIRN192 microRNA, human; C551411:MIRN212 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003474:Curcumin
keywords: Curcumin; Non-small cell lung cancer; Tet-on system; XIAP; miRNA; p53