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.
Highlights
Breast cancer is one of the most common clinical cancers in the world, and it is the main cause of cancer-related death in women [1]
The expression level of Bax was significantly increased and the Bcl-2 level was decreased in 231/PTX cells treated with PTX plus ursolic acid (UA) compared with the levels in cells treated with PTX only (Figure 1G).These results suggest that UA could reverse PTX resistance in breast cancer cells
It has been reported that miRNAs play a critical role in regulating gene expression during chemotherapy treatments, as miRNAs can directly target the protein-coding genes and can inhibit the genes required for signaling pathways or drug-induced apoptosis; multiple miRNAs are considered critical for the control of drug resistance [24]
Summary
Breast cancer is one of the most common clinical cancers in the world, and it is the main cause of cancer-related death in women [1]. As a microtubule stabilizer with good tolerability, PTX is widely used to treat breast cancer; its therapeutic efficacy is limited, due to the development of resistance [2]. A better understanding of the mechanisms underlying PTX resistance and attempts to reverse their resistance effectively are crucial for improving patients’ treatment options and prognosis. Our previous work [3] demonstrated that the expression of MyD88 was increased in breast cancer tissues, and its expression level was correlated with PTX resistance. Our data showed that the downregulation of MyD88 expression could significantly enhance PTX chemosensitivity in both breast cancer MCF-7 cells, lung cancer A549 cells [4], and ovarian cancer A2780 cells [5]. Searching for molecules or drugs that can effectively inhibit the expression of MyD88 can help reverse PTX resistance
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