Open AccessDihydrotanshinone-Induced NOX5 Activation Inhibits Breast Cancer Stem Cell through the ROS/Stat3 Signaling Pathway
Author(s) -
SuLim Kim,
Hack Sun Choi,
Ji Hyang Kim,
Dong Kee Jeong,
Ki-Seok Kim,
DongSun Lee
Publication year - 2019
Publication title -
oxidative medicine and cellular longevity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.494
H-Index - 93
eISSN - 1942-0900
pISSN - 1942-0994
DOI - 10.1155/2019/9296439
Subject(s) - signal transduction , microbiology and biotechnology , stat3 , cancer research , stem cell , chemistry , biology
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 CD44 high /CD24 low - 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.