Ferulin C triggers potent PAK1 and p21-mediated anti-tumor effects in breast cancer by inhibiting Tubulin polymerization in vitro and in vivo.

Abstract

Ferulin C, a natural sesquiterpene coumarin, isolated from the roots of Ferula ferulaeoides (Steud.) Korov, displaying potent antiproliferatory activity against breast cancer cells. This study aimed to elucidate the underlying molecular mechanisms of Ferulin C-induced breast cancer cells death in vitro and in vivo. Ferulin C presented potent antiproliferatory activity against MCF-7 and MDA-MB-231 cells and remarkable tubulin polymerization inhibitory activity (IC50 = 9.2 μM). Meanwhile, we predicted Ferulin C bind to the Colchicine site of tubulin through CETSA assay, molecular docking and molecular dynamics (MD) simulations. In immunofluorescence assay, Ferulin C disturbed the microtubule integrity and structure. Furthermore, Ferulin C stimulated significant cell cycle arrest in the G1/S period via p21Cip1/Waf1 - CDK2 signaling, induced classic cell apoptosis, impaired metastasis via down-regulating Ras-Raf-ERK and AKT-mTOR signaling. Intriguingly, Ferulin C treatment induced autophagy by ULK1 signaling to synergize with the inhibition of proliferation and metastasis. Based upon the RNAseq analysis, PAK1, as a novel essential modulator, was involved in the signaling regulated by Ferulin C -induced α/β-tubulin depolymerization. Additionally, Ferulin C displayed an acceptable antiproliferatory activity in an MCF-7 xenograft model without inducing obvious weight loss in the Ferulin C treated mice. Summarily, our findings substantiated that Ferulin C was a potent, colchicine site binding microtubule-destabilizing agent with anti-proliferation and anti-metastasis activity via PAK1 and p21-mediated signaling in breast cancer cells.

• Authors: Dahong Yao, Dabo Pan, Yongqi Zhen, Jian Huang, Jinhui Wang, Jin Zhang, Zhendan He
• Journal: Pharmacological research (Pharmacol Res) Vol. 152 Pg. 104605 (02 2020) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 31863866 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Coumarins
• Cyclin-Dependent Kinase Inhibitor p21
• Sesquiterpenes
• Tubulin
• Tubulin Modulators
• ferulin C
• p21-Activated Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Coumarins (pharmacology, therapeutic use)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Female
• Humans
• Mammary Neoplasms, Experimental (drug therapy, metabolism)
• Mice, Inbred BALB C
• Polymerization
• Sesquiterpenes (pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• Tubulin (metabolism)
• Tubulin Modulators (pharmacology, therapeutic use)
• p21-Activated Kinases (metabolism)