Regulation of E-cadherin localization by microtubule targeting agents

Rapid promotion of cortical E-cadherin through p130Cas/Src inhibition by eribulin

Nicholas F. Dybdal-Hargreaves, April L Risinger, Susan L Mooberry

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 a direct link between the initial disruption of the microtubule network and reversal of EMT phenotypes demonstrated by eribulin in long-term studies.

Original languageEnglish (US)
Pages (from-to)5545-5561
Number of pages17
JournalOncotarget
Volume9
Issue number5
DOIs
StatePublished - Jan 1 2018

Fingerprint

eribulin
Cadherins
Microtubules
Epithelial-Mesenchymal Transition
Pharmaceutical Preparations
src-Family Kinases
Interphase
Small Interfering RNA
Neoplasms
Phosphorylation

Keywords

  • E-cadherin
  • Epithelial-to-mesenchymal transition
  • Eribulin
  • Microtubule targeting agents
  • Paclitaxel

ASJC Scopus subject areas

  • Oncology

Cite this

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title = "Regulation of E-cadherin localization by microtubule targeting agents: Rapid promotion of cortical E-cadherin through p130Cas/Src inhibition by eribulin",
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 a direct link between the initial disruption of the microtubule network and reversal of EMT phenotypes demonstrated by eribulin in long-term studies.",
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