Oncotarget

Research Papers:

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

Zhiyu Wang, Neng Wang, Pengxi Liu, Qianjun Chen, Honglin Situ, Ting Xie, Jianxing Zhang, Cheng Peng, Yi Lin and Jianping Chen _

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Oncotarget. 2014; 5:7013-7026. https://doi.org/10.18632/oncotarget.2192

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Abstract

Zhiyu Wang1,2,*, Neng Wang2,*, Pengxi Liu1, Qianjun Chen1, Honglin Situ1, Ting Xie3, Jianxing Zhang1, Cheng Peng4, Yi Lin1, Jianping Chen2

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.


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