Paclitaxel-Induced Apoptosis Is BAK-Dependent, but BAX and BIM-Independent in Breast Tumor

Authors

Anna V. Miller, Virginia Commonwealth University
Mark A. Hicks, Virginia Commonwealth UniversityFollow
Wataru Nakajima, Virginia Commonwealth UniversityFollow
Amanda C. Richardson, Virginia Commonwealth UniversityFollow
Jolene J. Windle, Virginia Commonwealth UniversityFollow
Hisashi Harada, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2013

Journal/Book/Conference Title

PLOS ONE

Volume

8

DOI of Original Publication

10.1371/journal.pone.0060685

Comments

Originally published at http://dx.doi.org/10.1371/journal.pone.0060685

Date of Submission

November 2014

Abstract

Paclitaxel (Taxol)-induced cell death requires the intrinsic cell death pathway, but the specific participants and the precise mechanisms are poorly understood. Previous studies indicate that a BH3-only protein BIM (BCL-2 Interacting Mediator of cell death) plays a role in paclitaxel-induced apoptosis. We show here that BIM is dispensable in apoptosis with paclitaxel treatment using bim−/− MEFs (mouse embryonic fibroblasts), the bim−/− mouse breast tumor model, and shRNA-mediated down-regulation of BIM in human breast cancer cells. In contrast, both bak−/− MEFs and human breast cancer cells in which BAK was down-regulated by shRNA were more resistant to paclitaxel. However, paclitaxel sensitivity was not affected in bax−/−MEFs or in human breast cancer cells in which BAX was down-regulated, suggesting that paclitaxel-induced apoptosis is BAK-dependent, but BAX-independent. In human breast cancer cells, paclitaxel treatment resulted in MCL-1 degradation which was prevented by a proteasome inhibitor, MG132. A Cdk inhibitor, roscovitine, blocked paclitaxel-induced MCL-1 degradation and apoptosis, suggesting that Cdk activation at mitotic arrest could induce subsequent MCL-1 degradation in a proteasome-dependent manner. BAK was associated with MCL-1 in untreated cells and became activated in concert with loss of MCL-1 expression and its release from the complex. Our data suggest that BAK is the mediator of paclitaxel-induced apoptosis and could be an alternative target for overcoming paclitaxel resistance.

Rights

© 2013 Miller et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Is Part Of

VCU Philips Institute for Oral Health Research Publications