Inhibition of YAP/TAZ pathway contributes to the cytotoxicity of silibinin in MCF-7 and MDA-MB-231 human breast cancer cells.

Autor: Fu J; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China., Liu W; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China., Liu S; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China., Zhao R; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China., Hayashi T; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China; Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017, Japan., Zhao H; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China., Xiang Y; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China., Mizuno K; Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017, Japan., Hattori S; Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017, Japan., Fujisaki H; Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017, Japan., Ikejima T; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China; Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning, China. Electronic address: ikejimat@vip.sina.com.
Jazyk: angličtina
Zdroj: Cellular signalling [Cell Signal] 2024 Jul; Vol. 119, pp. 111186. Date of Electronic Publication: 2024 Apr 20.
DOI: 10.1016/j.cellsig.2024.111186
Abstrakt: Breast cancer is one of the most common cancers threatening women's health. Our previous study found that silibinin induced the death of MCF-7 and MDA-MB-231 human breast cancer cells. We noticed that silibinin-induced cell damage was accompanied by morphological changes, including the increased cell aspect ratio (cell length/width) and decreased cell area. Besides, the cytoskeleton is also destroyed in cells treated with silibinin. YAP/TAZ, a mechanical signal sensor interacted with extracellular pressure, cell adhesion area and cytoskeleton, is also closely associated with cell survival, proliferation and migration. Thus, the involvement of YAP/TAZ in the cytotoxicity of silibinin in breast cancer cells has attracted our interests. Excitingly, we find that silibinin inhibits the nuclear translocation of YAP/TAZ in MCF-7 and MDA-MB-231 cells, and reduces the mRNA expressions of YAP/TAZ target genes, ACVR1, MnSOD and ANKRD. More importantly, expression of YAP1 gene is negatively correlated with the survival of the patients with breast cancers. Molecular docking analysis reveals high probabilities for binding of silibinin to the proteins in the YAP pathways. DARTS and CETSA results confirm the binding abilities of silibinin to YAP and LATS. Inhibiting YAP pathway either by addition of verteporfin, an inhibitor of YAP/TAZ-TEAD, or by transfection of si-RNAs targeting YAP or TAZ further enhances silibinin-induced cell damage. While enhancing YAP activity by silencing LATS1/2 or overexpressing YAP S127/397A , an active form of YAP, attenuates silibinin-induced cell damage. These findings demonstrate that inhibition of the YAP/TAZ pathway contributes to cytotoxicity of silibinin in breast cancers, shedding lights on YAP/TAZ-targeted cancer therapies.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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