黄芪甲苷通过抑制 Vav3 介导的 Rac1/MAPK 信号通路抑制乳腺癌细胞侵袭。
Astragaloside IV inhibits breast cancer cell invasion by suppressing Vav3 mediated Rac1/MAPK signaling.
机构信息
Department of Breast Diseases, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Rd, Shanghai, China.
Department of Breast Diseases, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Rd, Shanghai, China.
出版信息
Int Immunopharmacol. 2017 Jan;42:195-202. doi: 10.1016/j.intimp.2016.10.001. Epub 2016 Dec 5.
BACKGROUND
Astragaloside IV (AS-IV), the major active triterpenoid in Radix Astragali, has shown anti-tumorigenic properties in certain cancers; however, its role in breast cancer remains unclear. The present study investigated the effects of AS-IV on breast cancer in vitro and in vivo and examined the underlying mechanisms.
METHODS
The effects of AS-IV on MDA-MB-231 cell proliferation, migration, invasion and metastasis were investigated by MTT and Transwell assays, and western blotting. In addition, an orthotopic mouse tumor model was established for in vivo experiments.
RESULTS
AS-IV inhibited the viability and invasive potential of MDA-MB-231 breast cancer cells, suppressed the activation of the mitogen activated protein kinase (MAPK) family members ERK1/2 and JNK, and downregulated matrix metalloproteases (MMP)-2 and -9. The effects of AS-IV were mediated by the downregulation of Vav3, a guanine nucleotide exchange factor, leading to decreased levels of activated Rac1, a Rho family GTPase. Vav3 overexpression promoted cell proliferation and invasion in vitro, whereas Vav3 silencing had the opposite effects. AS-IV suppressed orthotopic breast tumor growth and metastasis to the lungs, whereas ectopic expression of Vav3 reversed the inhibitory effect of AS-IV on cell viability, invasiveness, MAPK signaling and MMP expression.
CONCLUSION
The present results provide a mechanistic explanation for the antitumor effects of AS-IV and suggest its potential in the treatment of metastatic breast cancer.
背景
黄芪甲苷（AS-IV）是黄芪的主要活性三萜类化合物，已显示出在某些癌症中具有抗肿瘤特性；然而，其在乳腺癌中的作用尚不清楚。本研究探讨了 AS-IV 对乳腺癌的体内外作用及其潜在机制。
方法
通过 MTT 和 Transwell 分析以及 Western blot 检测，研究了 AS-IV 对 MDA-MB-231 细胞增殖、迁移、侵袭和转移的影响。此外，还建立了原位小鼠肿瘤模型进行体内实验。
结果
AS-IV 抑制 MDA-MB-231 乳腺癌细胞的活力和侵袭潜能，抑制丝裂原活化蛋白激酶（MAPK）家族成员 ERK1/2 和 JNK 的激活，并下调基质金属蛋白酶（MMP）-2 和 -9。AS-IV 的作用是通过下调鸟嘌呤核苷酸交换因子 Vav3 介导的，导致激活的 Rac1（Rho 家族 GTPase）水平降低。Vav3 过表达促进细胞在体外的增殖和侵袭，而 Vav3 沉默则产生相反的效果。AS-IV 抑制原位乳腺癌肿瘤的生长和向肺部的转移，而 Vav3 的异位表达则逆转了 AS-IV 对细胞活力、侵袭性、MAPK 信号和 MMP 表达的抑制作用。
结论
本研究结果为 AS-IV 的抗肿瘤作用提供了机制解释，并提示其在治疗转移性乳腺癌方面的潜力。
Zotero 插件