Icariin-induced inhibition of SIRT6/NF-κB triggers redox mediated apoptosis and enhances anti-tumor immunity in triple-negative breast cancer.

Abstract

Abnormal activation of the nuclear factor-kappa B (NF-κB) signaling pathway is closely implicated in triple-negative breast cancer growth, metastasis, and tumor immune escape. In this study, the anti-cancer effects of icariin, a natural flavonol glycoside, toward breast cancer cells and the underlying mechanisms were investigated. This investigation showed that icariin selectively inhibited proliferation and triggered apoptosis in breast cancer 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 the upregulated ratio of Bax/Bcl-2 and reactive oxygen species induction. Importantly, icariin impaired the activation of the NF-κB/EMT pathway, as evidenced by upregulation 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. Transcriptomic analysis verified that impairment of NF-κB led to the selective function of icariin in breast cancer cells. 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 the tumor immunosuppressive microenvironment. Together, these results showed that icariin could effectively trigger apoptosis and inhibit the 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.

• Authors: Linjiang Song, Xian Chen, Ling Mi, Chi Liu, Shaomi Zhu, Tianlin Yang, Xiaohong Luo, Qinxiu Zhang, Hua Lu, Xin Liang
• Journal: Cancer science (Cancer Sci) Vol. 111 Issue 11 Pg. 4242-4256 (Nov 2020) ISSN: 1349-7006 [Electronic] England
• PMID: 32926492 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Drugs, Chinese Herbal
• Flavonoids
• NF-kappa B
• Reactive Oxygen Species
• SIRT6 protein, human
• Sirtuins
• icariin

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Disease Models, Animal
• Drugs, Chinese Herbal (chemistry, pharmacology)
• Female
• Flavonoids (chemistry, pharmacology)
• Gene Expression Profiling
• Humans
• Mice
• Mitochondria (drug effects, metabolism)
• Models, Biological
• NF-kappa B (metabolism)
• Neoplasm Metastasis
• Neoplasm Staging
• Oxidation-Reduction (drug effects)
• Reactive Oxygen Species (metabolism)
• Sirtuins (metabolism)
• Transcription, Genetic
• Triple Negative Breast Neoplasms (drug therapy, etiology, metabolism, pathology)
• Xenograft Model Antitumor Assays