title: MicroRNA-25 regulates chemoresistance-associated autophagy in breast cancer cells, a process modulated by the natural autophagy inducer isoliquiritigenin.
abstract: Recent findings have revealed that dysregulated miRNAs contribute significantly to autophagy and chemoresistance. Pharmacologically targeting autophagy-related miRNAs is a novel strategy to reverse drug resistance. Here, we report a novel function of isoliquiritigenin (ISL) as a natural inhibitor of autophagy-related miR-25 in killing drug-resistant breast cancer cells. ISL induced chemosensitization, cell cycle arrest and autophagy, but not apoptosis, in MCF-7/ADR cells. ISL also promoted the degradation of the ATP-binding cassette (ABC) protein ABCG2 primarily via the autophagy-lysosome pathway. More importantly, miRNA 3.0 array experiments identified miR-25 as the main target of ISL in triggering autophagy flux. A mechanistic study validated that miR-25 inhibition led to autophagic cell death by directly increasing ULK1 expression, an early regulator in the autophagy induction phase. miR-25 overexpression was demonstrated to block ISL-induced autophagy and chemosensitization. Subsequent in vivo experiments showed that ISL had chemosensitizing potency, as revealed by an increase in LC3-II staining, the downregulation of ABCG2, a reduction in miR-25 expression and the activation of the miR-25 target ULK1. Overall, our results not only indicate that ISL acts as a natural autophagy inducer to increase breast cancer chemosensitivity, but also reveal that miR-25 functions as a novel regulator of autophagy by targeting ULK1.
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine; School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; These authors contributed equally to this work.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; These authors contributed equally to this work.
authors.forename: Neng
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine.
authors.forename: Pengxi
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine.
authors.forename: Qianjun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine.
authors.forename: Honglin
authors.initials: H
authors.lastname: Situ
authors.affiliation: Department of Dermatology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine.
authors.forename: Ting
authors.initials: T
authors.lastname: Xie
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine.
authors.forename: Jianxing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Deapartment of Pharmacology, Chengdu University of Traditional Chinese Medicine.
authors.forename: Cheng
authors.initials: C
authors.lastname: Peng
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D047188:Chalcones / Q000494:pharmacology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047188:Chalcones; C543351:MIRN25 microRNA, human; D035683:MicroRNAs; C040920:isoliquiritigenin