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.

MiR-15a and miR-16 induce autophagy and enhance chemosensitivity of Camptothecin

“…46 Inhibition of miR-25 leads to autophagic cell death and increases chemosensitivity to isoliquiritigenin in MCF-7/ADR cells. 47 Considering the paradoxical role of autophagy in cancer therapy, recognizing functional autophagy status in tumors will be required to direct the appropriate therapy.…”

AntimiR-30b Inhibits TNF-α Mediated Apoptosis and Attenuated Cartilage Degradation through Enhancing Autophagy

“…In recent studies, miRNAs have been reported to play a role in the regulation of autophagy [22,23]. For example, miR-30b, for which a predicted target site resides in the 3ʹ-UTR of autophagy-associated gene 12 (Atg12), has been shown to modulate autophagy in hepatic ischemia-reperfusion injury [24].…”

“…MiRNAs bind to their target mRNAs through incomplete base-pairing to the 3ʹ-untranslated region (3ʹ-UTR) or by binding to the amino acid coding sequence [13][14][15][16][17][18][19] It is now believed that each miRNA is capable of modulating the expression of hundreds of target genes, thereby affecting virtually all fundamental biological pathways and playing a critical role in a broad range of biological processes including proliferation, differentiation, apoptosis, and stress responses [20,21]. Recent findings have indicated some novel roles for miRNAs in the regulation of autophagy [22,23]. The 3ʹ-UTR of autophagy-associated gene 12 (Atg12) was reported to contain a predicted target site for miRNA-30b (miR-30b) and this miRNA has been shown to modulate autophagy in hepatic ischemia-reperfusion injury [24].…”

iRGD-modified lipid–polymer hybrid nanoparticles loaded with isoliquiritigenin to enhance anti-breast cancer effect and tumor-targeting ability

“…24,[31][32][33] However, in this project the effective dose was decreased to 25 mg/kg every 2 days in the 4T1-bearing nude-mouse model. Also, the administration method was intraperitoneal rather than IV injection, which was because the volume of the NPs was too large to use IV injections.…”

“…7 In very recent years, we have found a flavonoid, isoliquiritigenin (ISL; structure in Figure 1A), that is not only able to inhibit angiogenesis of breast cancer cells via the VEGF-VEGFR2 pathway 8 and prevent mammary carcinogenesis through WIF1 demethylation, 9 but can also chemosensitize breast cancer stem cells, 10 serving as an autophagy inducer regulating chemoresistance-associated autophagy. 11 In addition, studies have shown that ISL can treat breast cancer via NFκB signaling and the PI3K-Akt pathway, inhibiting p38 expression and downregulating AA-metabolizing enzymes. [12][13][14] This evidence has demonstrated that ISL can be a promising anti-breast cancer agent worthy of being…”