MAPK/ERK通路
癌症研究
p38丝裂原活化蛋白激酶
细胞凋亡
激酶
药理学
小窝蛋白1
化学
下调和上调
生物
生物化学
基因
作者
Yifeng Zheng,Yan Dai,Weiping Liu,Neng Wang,Youli Cai,Shengqi Wang,Fengxue Zhang,Pengxi Liu,Qianjun Chen,Zhiyu Wang
摘要
Abstract Accumulating evidence suggests that caveolin‐1 (CAV‐1) is a stress‐related oncotarget and closely correlated to chemoresistance. Targeting CAV‐1 might be a promising strategy to improve chemosensitivity for breast cancer treatment. Astragaloside IV (AS‐IV), a bioactive compound purified from Astragalus membranaceus , has been shown to exhibit multiple bioactivities, including anticancer. However, the involved molecular targets are still ambiguous. In this study, we investigated the critical role of CAV‐1 in mediating the chemosensitizing effects of AS‐IV to Taxol on breast cancer. We found that AS‐IV could enhance the chemosensitivity of Taxol with minimal direct cytotoxicity on breast cancer cell lines MCF‐7 and MDA‐MB‐231, as well as the nontumor mammary epithelial cell line MCF‐10A. AS‐IV was further demonstrated to aggravate Taxol‐induced apoptosis and G2/M checkpoint arrest. The phosphorylation of mitogen‐activated protein kinase (MAPK) signaling extracellular signal‐regulated kinase (ERK) and c‐Jun N‐terminal Kinase (JNK), except p38, was also abrogated by a synergistic interaction between AS‐IV and Taxol. Moreover, AS‐IV inhibited CAV‐1 expression in a dose‐dependent manner and reversed CAV‐1 upregulation induced by Taxol administration. Mechanism study further demonstrated that AS‐IV treatment triggered the eNOS/NO/ONOO − pathway via inhibiting CAV‐1, which led to intense oxidant damage. CAV‐1 overexpression abolished the chemosensitizing effects of AS‐IV to Taxol by inhibiting oxidative stress. In vivo experiments further validated that AS‐IV increased Taxol chemosensitivity on breast cancer via inhibiting CAV‐1 expression, followed by activation of the eNOS/NO/ONOO − pathway. Taken together, our findings not only suggested the potential of AS‐IV as a promising candidate to enhance chemosensitivity, but also highlighted the significance of CAV‐1 as the target to reverse cancer drug resistance.
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