// Zhiyu Wang 1,2,* , Neng Wang 2,* , Pengxi Liu 1 , Qianjun Chen 1 , Honglin Situ 1 , Ting Xie 3 , Jianxing Zhang 1 , Cheng Peng 4 , Yi Lin 1 , Jianping Chen 2 1 Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine 2 School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China 3 Department of Dermatology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine 4 Deapartment of Pharmacology, Chengdu University of Traditional Chinese Medicine * These authors contributed equally to this work Correspondence: Jianping Chen, email: // Keywords : Autophagy; Drug resistance; miRNA-25; ULK1; Isoliquiritigenin; Breast cancer Received : May 04, 2014 Accepted : July 07, 2014 Published : July 09, 2014 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.

MicroRNA-25 regulates chemoresistance-associated autophagy in breast cancer cells, a process modulated by the natural autophagy inducer isoliquiritigenin