Icariin suppresses proliferation and metastasis and enhances antitumor
immunity in triple-negative breast cancer via SIRT6/NF-κB signaling
pathway
Abstract
Background and purpose Constitutive activation of Nuclear factor kappa B
(NF-κB) signaling pathway is closely implicated in triple-negative
breast cancer (TNBC) growth, metastasis and tumor immune escape.
Therefore, the anti-cancer effects of icariin, a natural inhibitor of
NF-κB, towards breast cancer cells and the underlying mechanisms were
investigated. Experimental approaches Effects of cytotoxicity,
anti-proliferation, apoptotic induction, anti-migration and
anti-invasion of icariin were evaluated in TNBC cells and tumor mouse
model. The inhibitory effect of icariin on
SIRT6/NF-κB/epithelial-mesenchymal transition (EMT) signaling pathway
was investigated by western-blot and transcriptomic analysis. The
regulatory effect of icariin on tumor immunosuppressive microenvironment
was evaluated. Key results Icariin selectively inhibited proliferation
and triggered apoptosis in TNBC cells in a concentration- and
time-dependent manner, but exhibited little cytotoxicity in normal
breast cells. Moreover, icariin induced cell apoptosis via a
mitochondria-mediated pathway, as indicated by upregulated ratio of
Bax/Bcl-2 and ROS induction. Importantly, icariin impaired activation of
NF-κB/EMT pathway by upregulating expression of SIRT6, resulting in
inhibition of migration and invasion of breast cancer cells.
Additionally, oss-128167, an inhibitor of SIRT6, dramatically attenuated
anti-migration and anti-invasion effects of icariin. Notably, icariin
exhibited a significant tumor growth inhibition and anti-pulmonary
metastasis effect in a tumor mouse model of MDA-MB-231 and 4T1 cells by
regulating tumor immunosuppressive microenvironment. Conclusions and
implications Icariin could effectively trigger apoptosis and inhibit
migration of breast cancer cells via the SIRT6/NF-κB signaling pathway,
suggesting that icariin might serve as a potential candidate drug for
the treatment of breast cancer.