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

Amith SR, Wilkinson JM, Baksh S, Fliegel L - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.

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.

Show MeSH

Related in: MedlinePlus

Long-term invasion is dependent on the expression of NHE1 in MDA-MB-231 breast cancer cellsA, Representative image of 231-WT and 231-KO cells in 3-dimensional scaffold over 7 days in 10% serum; arrow shows the direction of invasion from top to bottom of the scaffold. B, Summary of results showing the number of invading cells [*P<0.001, N=3].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4359231&req=5

Figure 7: Long-term invasion is dependent on the expression of NHE1 in MDA-MB-231 breast cancer cellsA, Representative image of 231-WT and 231-KO cells in 3-dimensional scaffold over 7 days in 10% serum; arrow shows the direction of invasion from top to bottom of the scaffold. B, Summary of results showing the number of invading cells [*P<0.001, N=3].

Mentions: Finally, we examined the role of NHE1 in a study of 3-dimensional long-term invasion by breast cancer cells. Cells were seeded onto a Matrigel matrix-coated scaffold that enabled 3-dimensional growth and proliferation, mimicking cell growth and association with the extracellular matrix in vivo. NHE1 knock out cells (231-KO) cells did not survive in serum-deprived (0.2% serum) conditions for 7 days in this assay, so the analysis was limited to serum-supplemented conditions. Here, 231-WT cells grown in 10% serum showed significantly more invasion through and, greater proliferation within, the scaffold than 231-KO cells (Fig. 7).


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

Amith SR, Wilkinson JM, Baksh S, Fliegel L - Oncotarget (2015)

Long-term invasion is dependent on the expression of NHE1 in MDA-MB-231 breast cancer cellsA, Representative image of 231-WT and 231-KO cells in 3-dimensional scaffold over 7 days in 10% serum; arrow shows the direction of invasion from top to bottom of the scaffold. B, Summary of results showing the number of invading cells [*P<0.001, N=3].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359231&req=5

Figure 7: Long-term invasion is dependent on the expression of NHE1 in MDA-MB-231 breast cancer cellsA, Representative image of 231-WT and 231-KO cells in 3-dimensional scaffold over 7 days in 10% serum; arrow shows the direction of invasion from top to bottom of the scaffold. B, Summary of results showing the number of invading cells [*P<0.001, N=3].
Mentions: Finally, we examined the role of NHE1 in a study of 3-dimensional long-term invasion by breast cancer cells. Cells were seeded onto a Matrigel matrix-coated scaffold that enabled 3-dimensional growth and proliferation, mimicking cell growth and association with the extracellular matrix in vivo. NHE1 knock out cells (231-KO) cells did not survive in serum-deprived (0.2% serum) conditions for 7 days in this assay, so the analysis was limited to serum-supplemented conditions. Here, 231-WT cells grown in 10% serum showed significantly more invasion through and, greater proliferation within, the scaffold than 231-KO cells (Fig. 7).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.

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.

Show MeSH
Related in: MedlinePlus