Cryptotanshinone inhibits Blood-borne Metastasis in Triple-negative Breast Cancer via Downregulation of Claudin-1 Expression
Xiang Liu, Hong Lu, Wei Wang, Junchao Ma, Yong Zou, Jianjiang FuIntroduction:
Triple-negative breast cancer (TNBC) is aggressive with aberrant claudin-1 (CLDN1) expression. Cryptotanshinone (CTS) from Salvia miltiorrhiza has anti-cancer activity against ER-positive/low-CLDN1 cells but limited effect on ER-negative/low-CLDN1 cells. This study compares the effects of CTS on TNBC cells with low versus high CLDN1 expression and investigates the mechanisms involved.
Methods:
Orthotopic tumor models, detection of circulating tumor cells (CTCs), migration assays, immunoblotting, and gene knockdown/overexpression were performed.
Results:
CTS inhibited migration, CTCs, and metastasis in CLDN1-high MDA-MB-468 cells but not in CLDN1-low MDA-MB-231 cells. CTS reduced CLDN1 phosphorylation, suppressed Ezrin phosphorylation and its PODXL binding, and decreased p-Src, p-JNK, and p-Paxillin.
Discussion:
The anti-metastatic effect of CTS depends on CLDN1 expression status. Ezrin acts as a downstream effector of CLDN1, and Src as an upstream modulator, with CTS inhibiting Src activity without feedback from Ezrin.
Conclusion:
In TNBC cells with high CLDN1 expression, CTS markedly inhibits both in vitro migration and blood-borne metastasis in vivo, which is associated with the down-regulation of Src/Ezrin signaling.