Oncotarget

Research Papers:

Simultaneous inhibition of deubiquitinating enzymes (DUBs) and autophagy synergistically kills breast cancer cells

Rachel Isaksson Vogel _, Kathleen Coughlin, Alessandra Scotti, Yoshie Iizuka, Ravi Anchoori, Richard B.S. Roden, Mauro Marastoni and Martina Bazzaro

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Oncotarget. 2015; 6:4159-4170. https://doi.org/10.18632/oncotarget.2904

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Abstract

Rachel Isaksson Vogel1, Kathleen Coughlin2, Alessandra Scotti3, Yoshie Iizuka2, Ravi Anchoori4,5, Richard B. S. Roden4,5,6, Mauro Marastoni3, Martina Bazzaro1,2

1Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA

2Department of Obstetrics, Gynecology and Women's Heath, University of Minnesota, Minneapolis, Minnesota, USA

3Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy

4Department of Pathology, Johns Hopkins University, Baltimore, MD, USA

5Department of Oncology, Johns Hopkins University, Baltimore, MD, USA

6Department of Gynecology and Obstetrics, Johns Hopkins University, Baltimore, MD, USA

Correspondence to:

Martina Bazzaro, e-mail: mbazzaro@umn.edu

Keywords: Breast Cancer, Triple Negative Breast Cancer, Proteasome Inhibitors, Deubiquitinating Enzymes, Autophagy

Received: October 01, 2014     Accepted: December 11, 2014     Published: February 27, 2015

ABSTRACT

Breast cancer is one of the leading causes of cancer death among women in the United States. Patients expressing the estrogen and progesterone receptor (ER and PR) and human epidermal growth factor 2 (HER-2) tumor markers have favorable prognosis and efficacious therapeutic options. In contrast, tumors that are negative for these markers (triple-negative) have a disproportionate share of morbidity and mortality due to lack of a validated molecular target.

Deubiquitinating enzymes (DUBs) are a critical component of ubiquitin-proteasome-system degradation and have been shown to be differentially expressed and activated in a number of cancers, including breast, with their aberrant activity linked to cancer prognosis and clinical outcome. We evaluated the effect of the DUB inhibitors b-AP15 and RA-9 alone and in combination with early- and late-stage lysosomal inhibitors on cell viability in a panel of triple negative breast cancer (TNBC) cell lines.

Our results indicate small-molecule DUB inhibitors have a profound effect on TNBC viability and lead to activation of autophagy as a cellular mechanism to compensate for ubiquitin-proteasome-system stress. Treatment with sub-optimal doses of DUB and lysosome inhibitors synergistically kills TNBC cells. This supports the evaluation of DUB inhibition, in combination with lysosomal inhibition, as a therapeutic approach for the treatment of TNBC.


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