Ursolic Acid Reverses the Chemoresistance of Breast Cancer Cells to Paclitaxel by Targeting MiRNA-149-5p/MyD88

Abstract

Paclitaxel (PTX) is widely used as a front-line chemotherapy for breast cancer treatment. However, its clinical applications are limited by the development of chemoresistance. The objective of this study was to investigate the reversal effects of ursolic acid (UA) on PTX resistance and the possible mechanisms in breast cancer. The role of miRNA-149-5p/MyD88 in the regulation of PTX resistance was investigated by the transfection of breast cancer cells with MDA-MB-231 (231) and MDA-MB-231/PTX-resistance (231/PTX) with lentiviruses carrying the MyD88 gene, shRNA specific for MyD88, the miR-149-5p gene, and shRNA specific for miR-149-5p. The PTX sensitivity was assessed by a CCK-8 assay. qRT-PCR and Western blot analyses were used to detect changes in the mRNA and protein levels. Flow cytometry was used to measure the rate of cell apoptosis. A luciferase activity assay was used to detect the binding site of miR-149-5p on the 3′UTR of MyD88. 231/PTX cells were injected into the flanks of female athymic nude mice, and the mice were randomly divided into the five following groups: PBS, PTX (low), PTX (high), UA, and PTX+UA. Our data show that UA reversed the resistance of breast cancer 231/PTX cells to PTX in vitro and in vivo . UA treatment significantly increased the expression of miR-149-5p, which was lower in 231/PTX cells than in 231 cells. Furthermore, the overexpression of miR-149-5p increased the sensitivity of 231/PTX cells to PTX treatment, whereas the knockdown of the miR-149-5p gene attenuated the effects of UA on the regulation of PTX sensitivity. A luciferase assay demonstrated that miR-149-5p could directly regulate the transcriptional activity of MyD88, a known PTX-resistance gene, by targeting the 3′UTR of MyD88. Meanwhile, the downregulation of MyD88 through the overexpression of miR-149-5p or UA treatment inhibited the activation of the Akt signaling pathway in 231/PTX cells. Thus, our data indicate that UA can reverse PTX resistance by targeting the miRNA-149-5p/MyD88 axis in breast cancer cells.

Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer

“…The miRNA-149 plays a significant role in suppressing different oncogenes and is frequently downregulated in BC. Overexpression studies with miRNA-149 demonstrated an inhibition of PI3K/AKT signaling pathway and MyD88 and a reverse of resistant to sensitive phenotype [ 168 ]. Additionally, an alkylating agent temozolomide exerted its anticancer effect by downregulating glucose metabolism.…”

The miRNA‐149‐5p/MyD88 axis is responsible for ursolic acid‐mediated attenuation of the stemness and chemoresistance of non‐small cell lung cancer cells

“…Although miRNAs only account for 1% of human genes, they can modulate up to 30% of human genes, making them the critical epigenetic regulators. Previous studies have identified the miR‐149/MyD88 axis in macrophages and breast cancer cells; however, it is still unclear whether this axis exists in NSCLC cells and regulates the stemness of NSCLC cells.…”

Ursolic Acid Suppresses Cholesterol Biosynthesis and Exerts Anti-Cancer Effects in Hepatocellular Carcinoma Cells

“…Here, this study found that UA, at a concentration of 10–20 μM, strongly inhibits cell viability in SK-HEP-1 (Figure 4A), Huh7 (Figure 4B), and Hep3B (Figure 4C) cells. Although the regulatory mechanism by which UA exerts anti-proliferative effects is not clear, large numbers of previous evidences have also shown that UA attenuates cell growth in multiple types of cancer cells, such as colorectal [11], breast [55], gastric [56], and melanoma [57]. Consistently, our results also show that UA was sufficient to decrease cell viability in lung (A549 and H1666), breast (MCF7 and MDA-MB-231), melanoma (A375 and A2058) and cervical (HeLa) cancer cells (Figure 4D).…”