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.
Highlights
Breast cancer is the most common malignancy and the second leading cause of cancer death in women worldwide
To determine whether ISL had chemosensitizing effects on drug-resistant breast cancer cells, we tested the synergistic effects of ISL and the chemotherapeutic drug epirubicin, which is usually administered as the first-line chemotherapy for breast cancer
We revealed that the natural chalcone-type compound ISL aggravated autophagy in drug-resistant breast cancer cells, which was accompanied by a G2/M checkpoint arrest and the downregulation of ABCG2 expression
Summary
Breast cancer is the most common malignancy and the second leading cause of cancer death in women worldwide. With the development of multidisciplinary treatments, the 5-year survival rate of breast cancer has greatly been improved. There are still 500,000 breast cancer deaths per year worldwide [1]. 40% of all breast cancer patients experience a recurrence, of which 10–20% are local and 60–70% are distant metastases [2]. Drug resistance is considered a major factor influencing breast cancer clinical outcomes. Current progress in finding a potent, selective agent to overcome cancer drug resistance has been slow and challenging [3]. How to effectively promote breast cancer chemosensitivity has become an urgent issue worldwide
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