Amith Schammim Ray, Wilkinson Jodi Marie, Baksh Shairaz, Fliegel Larry
Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
Department of Pediatrics, Biochemistry and Oncology, Alberta Inflammatory Bowel Disease Consortium, University of Alberta, Edmonton, Alberta, Canada.
Oncotarget. 2015 Jan 20;6(2):1262-75. doi: 10.18632/oncotarget.2860.
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.
钠氢交换体1型（NHE1）活性失调是发生肿瘤形成和转移的细胞的一个标志，而肿瘤形成和转移是患者死亡的主要原因。酸性肿瘤微环境被认为会促进对化疗药物耐药性的产生，并促进细胞外基质重塑从而导致转移。在此，我们研究了NHE1作为转移性乳腺癌紫杉醇化疗中的一种辅助靶点。我们构建了高侵袭性三阴性MDA-MB-231乳腺癌细胞的稳定NHE1基因敲除细胞系。NHE1基因敲除细胞的增殖与亲本细胞相当，但在体外其迁移和侵袭率显著降低。与亲本MDA-MB-231细胞相比，无胸腺裸鼠体内异种移植瘤的生长也显著减少。NHE1表达缺失还增加了基因敲除细胞对紫杉醇介导的细胞死亡的敏感性。NHE1抑制与紫杉醇联合使用，导致三阴性乳腺癌细胞的活力、迁移和侵袭能力显著降低，但对激素受体阳性的管腔型MCF7细胞没有影响。我们的数据表明，NHE1在三阴性乳腺癌转移中起关键作用，其化学抑制可提高紫杉醇在体外的疗效，突出了NHE1作为乳腺癌化疗中一种新型潜在辅助靶点的地位。
