Regulation of E-cadherin localization by microtubule targeting agents: rapid promotion of cortical E-cadherin through p130Cas/Src inhibition by eribulin

Oncotarget
Nicholas F Dybdal-HargreavesSusan L Mooberry

Abstract

Microtubule targeting agents (MTAs) are some of the most effective anticancer drugs used to treat a wide variety of adult and pediatric cancers. Building evidence suggests that these drugs inhibit interphase signaling events and that this contributes to their anticancer actions. The effects of diverse MTAs were evaluated following a 2 hour incubation with clinically relevant concentrations to test the hypothesis that these drugs rapidly and differentially disrupt epithelial-to-mesenchymal transition (EMT)-related signaling. The MTAs rapidly promoted the cortical localization of internal pools of E-cadherin in HCC1937 breast cancer cells, with the most robust effects observed with the microtubule destabilizers eribulin and vinorelbine. Cortical E-cadherin localization was also promoted by the Src kinase inhibitor dasatinib or by siRNA-mediated depletion of the p130Cas scaffold. Mechanistic studies demonstrate that eribulin disrupts the interaction between p130Cas and Src, leading to decreased cortical Src phosphorylation that precedes the accumulation of cortical E-cadherin. These results suggest that microtubules can be actively co-opted by cancer cells to inhibit cortical E-cadherin localization, a hallmark of EMT, and provide...Continue Reading

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Citations

May 21, 2019·Expert Opinion on Drug Safety·Jose Manuel Perez-Garcia, Javier Cortes
Nov 12, 2020·Biology·Jaya Aseervatham
May 12, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Jingshan CaiShengjun Wang
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Jul 28, 2021·Molecular Pharmacology·Charles S FermainttApril L Risinger

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Methods Mentioned

BETA
X-ray
xenograft
co-immunoprecipitation
as

Software Mentioned

Genetica
Prism
GraphPad
Nikon

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