Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 234, Issue 4, Pages 4277-4290Publisher
WILEY
DOI: 10.1002/jcp.27196
Keywords
astragaloside IV (AS-IV); breast cancer; caveolin-1 (CAV-1); chemosensitivity; nitrative stress
Categories
Funding
- Post-doctoral Science Foundation of China [2017M612644, 2017M622669]
- Guangdong Science and Technology Department [2016A030306025]
- Combined Scientific Project - Guangdong Provincial Science and Technology Agency [2014A020221047]
- Combined Scientific Project - Guangdong Provincial Academy of Traditional Chinese Medicine [2014A020221047]
- Pearl River S&T Nova Program of Guangzhou [201506010098]
- Specific Research Fund for TCM Science and Technology of Guangdong Provincial Hospital of Chinese Medicine [YN2014ZHR210]
- High-level Personnel of Special Support Program [A1-3002-16-111-003]
- International Postdoctoral Exchange Fellowship Program [2016M592585]
- High-level university construction project [A1-AFD018171Z11102, A1-AFD018161Z1510, A1-AFD018171Z11101]
- Research Project of Traditional Chinese Medicine Bureau of Guangdong Province [20182044, 20181132]
- China Postdoctoral Science Foundation [2016M592585]
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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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