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.
Highlights
In normal and neoplastic cells, the maintenance of pH homeostasis is regulated by the Na+/H+ exchanger isoform one (NHE1)
When stimulated 231WT, 231 Na+/H+ exchanger isoform 1 (NHE1)-knockout cells (231-KO) or MDA-MB-468 cells were treated with paclitaxel in the presence or absence of NHE1 inhibitors, EMD87580 or HMA, we found a significant reduction in the number of invading 231-wild type (231-WT) and MDA-MB-468 cells after 24 hours (P
WT cells grown in 10% serum showed significantly more invasion through and, greater proliferation within, the scaffold than 231-KO cells (Fig. 7). Both established and novel chemotherapeutic strategies can have limited success in the treatment of metastatic cancer, especially due to the development of multidrug resistance [23]. This is apparent in the treatment of triple-negative breast cancer, which is negative for the expression of estrogen and progesterone receptors and Human epithelial growth factor receptor 2 (HER2), and not susceptible to hormone or HER2-targeted therapy
Summary
In normal and neoplastic cells, the maintenance of pH homeostasis is regulated by the Na+/H+ exchanger isoform one (NHE1). NHE1 is a ubiquitously expressed, integral plasma membrane protein comprised of a membrane-traversing domain that facilitates ion flux, and a cytoplasmic C-terminal domain that regulates exchanger activity. Several intracellular proteins and lipids (e.g. PIP2, CHP1/2/3, actin binding proteins ezrin-radixin-moesin, calmodulin, carbonic anhydrase II) regulate Na+/H+ exchange via interaction with the C-terminal tail of NHE1 [3]. Whether all these protein and lipid associations are retained in breast cancer cells is not clear [4]
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