乌索酸在≥10 μM的剂量下显着抑制MDA-MB-231细胞的增殖，且呈剂量依赖性。在低于（29.87±2.60） μM的浓度下未观察到细胞毒性。进行乌索酸处理可抑制整个细胞和细胞核中Nrf2、p-Nrf2，和NQO1的表达，而Keap1的表达上调。Nrf2 mRNA水平未观察到显着差异，表明乌索酸不是通过mRNA而是通过翻译后修饰机制降低Nrf2表达。此外，乌索酸消除了EGF诱导的p-Nrf2及其下游NQO1和SOD1酶。但是，EGF或p-EGFR对Keap1的表达没有影响。这些结果表明，乌索酸对MDA-MB-231细胞的增殖抑制作用可能是部分通过Keap1/Nrf2通路和EGFR/Nrf2通路下调 Nrf2。
Abstract
Antiproliferative Activity of Ursolic Acid in MDA-MB-231 Human Breast Cancer Cells through Nrf2 Pathway Regulation
Xi Zhang, Tong Li, Er Sheng Gong, and Rui Hai Liu
Department of Food Science, Cornell University, 245 Stocking Hall, Ithaca, New York 14853-7201, United States
The potential mechanisms of action of ursolic acid (UA) in regulating cell proliferation in MDA-MB-231 human breast cancer cells through Nrf2 pathway were investigated. UA significantly inhibited the proliferation of MDA-MB-231 cells at a dose ≥10 μM in a dose-dependent manner, and no cytotoxicity was observed at concentrations below 29.87 ± 2.60 μM. The expressions of Nrf2 and p-Nrf2, in whole cell and nucleus, and NQO1 were inhibited by UA treatment, whereas the Keap1 expression was upregulated. No significant difference was observed in the Nrf2 mRNA levels, indicating that UA reduced Nrf2 expression not through mRNA but through a post-translational mechanism. Additionally, EGF-induced p-Nrf2 and its downstream NQO1 and SOD1 enzymes were abolished by UA. However, EGF or p-EGFR had no effect on the expressions of Keap1. These results suggested that the proliferative inhibitory effect of UA might be partially through downregulating Nrf2 via the Keap1/Nrf2 pathway and EGFR/Nrf2 pathway in MDA-MB-231 cells.
