Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Cancer Chemother Pharmacol. 2021 May;87(5):647-656. doi: 10.1007/s00280-021-04238-w. Epub 2021 Feb 5.
Honokiol, a natural phenolic compound derived from Magnolia plants, is a promising anti-tumor compound that exerts a wide range of anti-cancer effects. Herein, we investigated the effect of honokiol on doxorubicin resistance in breast cancer.
Doxorubicin-sensitive (MCF-7 and MDA-MB-231) and doxorubicin-resistant (MCF-7/ADR and MDA-MB-231/ADR) breast cancer cell lines were treated with doxorubicin in the absence or presence of honokiol; then, the following tests were performed: flow cytometry for cell apoptosis, WST-1 assay for cell viability, qPCR and western blot for the expression of miR-188-5p, FBXW7, and c-Myc. MiR-188-5p mimic, miR-188-5p inhibitor, siFBXW7, and c-Myc plasmids were transfected into cancer cells to evaluate whether miR-188-5p and FBXW7/c-Myc signaling are involved in the effect of honokiol on doxorubicin resistance in breast cancer. A dual luciferase reporter system was used to study the direct interaction between miR-188-5p and FBXW7.
Honokiol sensitized doxorubicin-resistant breast cancer cells to doxorubicin-induced apoptosis. Mechanically, upregulation of miR-188-5p was associated with doxorubicin resistance, and honokiol enhanced doxorubicin sensitivity by downregulating miR-188-5p. FBXW7 was confirmed to be a direct target gene of miR-188-5p. FBXW7/c-Myc signaling was involved in the chemosensitization effect of honokiol. Honokiol induced apoptosis in MCF-7/ADR and MDA-MB-231/ADR cells. However, FBXW7 silencing or c-Myc transfection resulted in resistance to the honokiol-induced apoptotic effect.
These findings suggest that downregulation of miR-188-5p by honokiol enhances doxorubicin sensitivity through FBXW7/c-Myc signaling in human breast cancer. Our study finds an important role of miR-188-5p in the development of doxorubicin resistance in breast cancer, and enriches our understanding of the mechanism of action of honokiol in cancer therapy.
厚朴酚是一种天然酚类化合物，来源于木兰属植物，是一种有前途的抗肿瘤化合物，具有广泛的抗癌作用。在此，我们研究了厚朴酚对乳腺癌多柔比星耐药性的影响。
用多柔比星处理多柔比星敏感（MCF-7 和 MDA-MB-231）和多柔比星耐药（MCF-7/ADR 和 MDA-MB-231/ADR）乳腺癌细胞系；然后进行以下测试：流式细胞术检测细胞凋亡，WST-1 法检测细胞活力，qPCR 和 Western blot 检测 miR-188-5p、FBXW7 和 c-Myc 的表达。转染 miR-188-5p 模拟物、miR-188-5p 抑制剂、siFBXW7 和 c-Myc 质粒，评估 miR-188-5p 和 FBXW7/c-Myc 信号是否参与厚朴酚对乳腺癌多柔比星耐药性的影响。双荧光素酶报告系统用于研究 miR-188-5p 与 FBXW7 之间的直接相互作用。
厚朴酚使多柔比星耐药乳腺癌细胞对多柔比星诱导的凋亡敏感。机制上，miR-188-5p 的上调与多柔比星耐药有关，厚朴酚通过下调 miR-188-5p 增强多柔比星的敏感性。FBXW7 被确认为 miR-188-5p 的直接靶基因。FBXW7/c-Myc 信号参与了厚朴酚的化疗增敏作用。厚朴酚诱导 MCF-7/ADR 和 MDA-MB-231/ADR 细胞凋亡。然而，FBXW7 沉默或 c-Myc 转染导致对厚朴酚诱导的凋亡作用产生抗性。
这些发现表明，厚朴酚通过下调 miR-188-5p 通过 FBXW7/c-Myc 信号增强人乳腺癌多柔比星的敏感性。我们的研究发现 miR-188-5p 在乳腺癌多柔比星耐药发展中的重要作用，丰富了我们对厚朴酚在癌症治疗中作用机制的理解。
