Astragaloside IV enhances taxol chemosensitivity of breast cancer via caveolin‐1‐targeting oxidant damage. Issue 4 (26th August 2018)

• Record Type: Journal Article
• Authors: Zheng, Yifeng; Dai, Yan; Liu, Weiping; Wang, Neng; Cai, Youli; Wang, Shengqi; Zhang, Fengxue; Liu, Pengxi; Chen, Qianjun; Wang, Zhiyu
• Is Part Of: Journal of cellular physiology. Volume 234:Issue 4(2019:Apr.)
• Page Start: 4277
• Page End: 4290
• Publication Date: 2018-08-26
• Subjects: astragaloside IV (AS‐IV) -- breast cancer -- caveolin‐1 (CAV‐1) -- chemosensitivity -- nitrative stress; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.27196
• Languages: English
• ISSNs: 0021-9541

Abstract

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. Abstract : Astragaloside IV (AS‐IV) promotes chemosensitivity via downregulating the expression of caveolin‐1 (CAV‐1) and subsequently activates nitrative stress response. Decreased level of CAV‐1 overexpresses eNOS and facilitates NO formation, thereby improving ONOO − production and leading to cell death. 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.