End-binding protein 1 stimulates paclitaxel sensitivity in breast cancer by promoting its actions toward microtubule assembly and stability.

Dengwen Li,Ruming Liu,Youguang Luo,Jie Ran,Jun Zhou,Bing Yan,Jie Chen,Min Liu,Zhu Liu,Xin Dong

doi:10.1007/s13238-014-0053-0

Abstract

Paclitaxel is a microtubule-targeting agent widely used for the treatment of many solid tumors. However, patients show variable sensitivity to this drug, and effective diagnostic tests predicting drug sensitivity remain to be investigated. Herein, we show that the expression of end-binding protein 1 (EB1), a regulator of microtubule dynamics involved in multiple cellular activities, in breast tumor tissues correlates with the pathological response of tumors to paclitaxel-based chemotherapy. In vitro cell proliferation assays reveal that EB1 stimulates paclitaxel sensitivity in breast cancer cell lines. Our data further demonstrate that EB1 increases the activity of paclitaxel to cause mitotic arrest and apoptosis in cancer cells. In addition, microtubule binding affinity analysis and polymerization/depolymerization assays show that EB1 enhances paclitaxel binding to microtubules and stimulates the ability of paclitaxel to promote microtubule assembly and stabilization. These findings thus reveal EB1 as a critical regulator of paclitaxel sensitivity and have important implications in breast cancer chemotherapy.

Highlights

Microtubules are a component of the cytoskeleton and play a crucial role in diverse cellular activities
We show that the expression of end-binding protein 1 (EB1), a regulator of microtubule dynamics involved in multiple cellular activities, in breast tumor tissues correlates with the pathological response of tumors to paclitaxel-based chemotherapy
To understand the underlying mechanism of how EB1 increases paclitaxel-mediated microtubule assembly and Microtubule dynamics are critical for many cellular activities, such as cell division, cell migration, and cell polarization

Summary

Introduction

Microtubules are a component of the cytoskeleton and play a crucial role in diverse cellular activities. EB1 tracks the plus ends of growing microtubules and thereby regulates microtubule dynamic instability (Akhmanova and Steinmetz, 2008; Schuyler and Pellman, 2001). Recent studies point out that EB1 regulates microtubule dynamics through promoting persistent microtubule growth (Bieling et al, 2007; Li et al, 2011; Strickland et al, 2005; Wen et al, 2004; Zovko et al, 2008). EB1 is a cofactor for many other microtubule-interacting proteins, which interact with EB1 directly or require EB1 for their efficient plus-end accumulation (Akhmanova and Steinmetz, 2008; Bieling et al, 2007; Dragestein et al, 2008; Galjart, 2010; Honnappa et al, 2009; Jiang and Akhmanova, 2011; Kronja et al, 2009)

Methods

Results

Conclusion