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.
Highlights
Microtubule targeting agents (MTAs) are highly effective anticancer drugs that remain a mainstay in the treatment of adult and pediatric cancers [1]
Representative images for the time and concentrationdependent effects of eribulin and paclitaxel on microtubule structures in HCC1937 (Figures 1, 2) and in BT-549 cells (Supplementary Figures 1, 2) are presented. These results show that a 2 hour treatment with eribulin or paclitaxel causes a concentration-dependent disruption of interphase microtubules in both cell lines (Figure 1, Supplementary Figure 1)
These studies were designed to evaluate the early effects of microtubule disruption on oncogenic signaling pathways that drive epithelial-to-mesenchymal transition (EMT), which is associated with a poor prognosis in metastatic breast cancer [49]
Summary
Microtubule targeting agents (MTAs) are highly effective anticancer drugs that remain a mainstay in the treatment of adult and pediatric cancers [1]. Microtubule destabilizers with clinical anticancer activities include the vinca alkaloids and eribulin [3]. Divergent clinical responses to different MTAs was further highlighted during the development of eribulin, a MTA that provided a survival benefit as third-line therapy in patients with locally recurrent or metastatic breast cancer who had been treated previously with a taxane and an anthracycline [6]. These findings suggest that there are differences among MTAs that result in variations in patient responses. Identification of the mechanisms underlying these differences could lead to use of specific MTAs in patients with defined tumor characteristics to optimize the rational use of these drugs
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