Dihydrotanshinone-Induced NOX5 Activation Inhibits Breast Cancer Stem Cell through the ROSStat3 Signaling Pathway

الملخص EN

Cancer stem cells (CSCs) are known to mediate metastasis and recurrence and are therefore a promising therapeutic target.

In this study, we found that dihydrotanshinone (DHTS) inhibits CSC formation.

DHTS inhibited mammosphere formation in a dose-dependent manner and showed significant tumor growth inhibition in a xenograft model.

This compound reduced the CD44high/CD24low- and aldehyde dehydrogenase- (ALDH-) expressing cell population and the self-renewal-related genes Nanog, SOX2, OCT4, C-Myc, and CD44.

DHTS induced NOX5 activation by increasing calcium, and NOX5 activation induced reactive oxygen species (ROS) production.

ROS production reduced the nuclear phosphorylation levels of Stat3 and secreted IL-6 levels in the mammospheres.

DHTS deregulated the dynamic equilibrium from non-stem cancer cells to CSCs by dephosphorylating Stat3 and decreasing IL-6 secretion and inhibiting CSC formation.

These novel findings showed that DHTS-induced ROS deregulated the Stat3/IL-6 pathway and induced CSC death.

NOX5 activation by DHTS inhibits CSC formation through ROS/Stat3/IL-6 signaling, and DHTS may be a promising potential therapeutic agent against breast CSCs.