title: Inhibition of miR-17 and miR-20a by oridonin triggers apoptosis and reverses chemoresistance by derepressing BIM-S.
abstract: Cancer cell chemoresistance arises in part through the acquisition of apoptotic resistance. Leukemia cells resistant to chemotherapy-induced apoptosis have been found to be sensitive to oridonin, a natural agent with potent anticancer activity. To investigate its mechanisms of action in reversing chemoresistance, we compared the response of human leukemia cells with oridonin and the antileukemia drugs Ara-C and VP-16. Compared with HL60 cells, K562 and K562/ADR cells displayed resistance to apoptosis stimulated by Ara-C and VP-16 but sensitivity to oridonin. Mechanistic investigations revealed that oridonin upregulated BIM-S by diminishing the expression of miR-17 and miR-20a, leading to mitochondria-dependent apoptosis. In contrast, neither Ara-C nor VP-16 could reduce miR-17 and miR-20a expression or could trigger BIM-S-mediated apoptosis. Notably, silencing miR-17 or miR-20a expression by treatment with microRNA (miRNA; miR) inhibitors or oridonin restored sensitivity of K562 cells to VP-16. Synergistic effects of oridonin and VP-16 were documented in cultured cells as well as mouse tumor xenograft assays. Inhibiting miR-17 or miR-20a also augmented the proapoptotic activity of oridonin. Taken together, our results identify a miRNA-dependent mechanism underlying the anticancer effect of oridonin and provide a rationale for its combination with chemotherapy drugs in addressing chemoresistant leukemia cells.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Hengyou
authors.initials: H
authors.lastname: Weng
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Huang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Dong
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Panpan
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, PR China lssqlh@mail.sysu.edu.cn lsszh@mail.sysu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, PR China lssqlh@mail.sysu.edu.cn lsszh@mail.sysu.edu.cn.
authors.forename: Lianghu
authors.initials: L
authors.lastname: Qu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D003561:Cytarabine / Q000494:pharmacology; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D018613:Microscopy, Confocal; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D045786:Diterpenes, Kaurane; C524941:MIRN17 microRNA, human; C534451:MIRN20a microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D003561:Cytarabine; C011959:oridonin; D005047:Etoposide