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: Zhiyu Wang, Neng Wang, Pengxi Liu, Qianjun Chen, Honglin Situ, Ting Xie, Jianxing Zhang, Cheng Peng, Yi Lin, Jianping Chen
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 16 Pg. 7013-26 (Aug 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25026296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chalcones
• MIRN25 microRNA, human
• MicroRNAs
• isoliquiritigenin

Topics

• Animals
• Autophagy (drug effects, genetics)
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Chalcones (pharmacology)
• Down-Regulation
• Drug Resistance, Neoplasm (genetics)
• Female
• Humans
• MCF-7 Cells
• Mice
• Mice, Inbred NOD
• Mice, SCID
• MicroRNAs (genetics)
• Xenograft Model Antitumor Assays