Eribulin rapidly inhibits TGF-β-induced Snail expression and can induce Slug expression in a Smad4-dependent manner

Area of Science:

• Oncology
• Cell Biology
• Molecular Biology

Background:

• Anticancer effects of microtubule targeting agents extend beyond antimitotic activity to include modulation of oncogenic signaling pathways.
• Microtubule-dependent signaling plays a crucial role in cancer progression, particularly in processes like epithelial-to-mesenchymal transition (EMT).

Purpose of the Study:

• To investigate the impact of microtubule targeting agents on the regulators of transforming growth factor-beta (TGF-β)-induced EMT in breast cancer.
• To elucidate the mechanisms by which these agents influence key EMT-transcription factors, Snail and Slug.

Main Methods:

• Utilized breast cancer cell lines for experiments.
• Employed high-content imaging, gene and protein expression analysis, siRNA-mediated knockdown, and chromatin immunoprecipitation.
• Assessed the effects on Snail and Slug expression and their relationship with Smad proteins and TGF-β signaling.

Main Results:

• Microtubule targeting agents differentially altered Snail and Slug expression.
• Eribulin, vinorelbine, and ixabepalone inhibited TGF-β-mediated Snail expression by disrupting Smad2/3 nuclear localization, while paclitaxel did not.
• Eribulin and vinorelbine increased Slug expression independently of TGF-β in cells with low Smad4, via microtubule depolymerization-induced c-Jun.

Conclusions:

• Identified a mechanism for eribulin to reverse EMT through microtubule disruption, potentially applicable in preclinical models and patients.
• High Smad4 levels may serve as a predictive biomarker for response to certain microtubule targeting agents.
• Highlighted distinct effects of different microtubule targeting drugs on EMT regulators, suggesting potential for more rational drug selection.