Oncotarget

Research Papers:

The Na+/H+ exchanger (NHE1) as a novel co-adjuvant target in paclitaxel therapy of triple-negative breast cancer cells

Schammim Ray Amith, Jodi Marie Wilkinson, Shairaz Baksh and Larry Fliegel _

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Oncotarget. 2015; 6:1262-1275. https://doi.org/10.18632/oncotarget.2860

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Abstract

Schammim Ray Amith1, Jodi Marie Wilkinson1, Shairaz Baksh2 and Larry Fliegel1

1 Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada

2 Department of Pediatrics, Biochemistry and Oncology, Alberta Inflammatory Bowel Disease Consortium, University of Alberta, Edmonton, Alberta, Canada

Correspondence:

Larry Fliegel, email:

Keywords: NHE1, Paclitaxel, Triple-negative breast cancer, Metastasis, pH regulation

Received: October 15, 2014 Accepted: November 25, 2014 Published: November 26, 2014

Abstract

Dysregulation of Na+/H+ exchanger isoform one (NHE1) activity is a hallmark of cells undergoing tumorigenesis and metastasis, the leading cause of patient mortality. The acidic tumor microenvironment is thought to facilitate the development of resistance to chemotherapy drugs and to promote extracellular matrix remodeling leading to metastasis. Here, we investigated NHE1 as a co-adjuvant target in paclitaxel chemotherapy of metastatic breast cancer. We generated a stable NHE1-knockout of the highly invasive, triple-negative, MDA-MB-231 breast cancer cells. The NHE1-knockout cells proliferated comparably to parental cells, but had markedly lower rates of migration and invasion in vitro. In vivo xenograft tumor growth in athymic nude mice was also dramatically decreased compared to parental MDA-MB-231 cells. Loss of NHE1 expression also increased the susceptibility of knockout cells to paclitaxel-mediated cell death. NHE1 inhibition, in combination with paclitaxel, resulted in a dramatic decrease in viability, and migratory and invasive potential of triple-negative breast cancer cells, but not in hormone receptor-positive, luminal MCF7 cells. Our data suggest that NHE1 is critical in triple-negative breast cancer metastasis, and its chemical inhibition boosts the efficacy of paclitaxel in vitro, highlighting NHE1 as a novel, potential co-adjuvant target in breast cancer chemotherapy.


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