TY - JOUR
T1 - Inhibition of pH regulation as a therapeutic strategy in hypoxic human breast cancer cells
AU - Meehan, James
AU - Ward, Carol
AU - Turnbull, Arran
AU - Bukowski-Wills, Jimi
AU - Finch, Andrew
AU - Jarman, Edward J.
AU - Xintaropoulou, Chrysi
AU - Martinez-Perez, Carlos
AU - Gray, Mark
AU - Pearson, Matthew
AU - Mullen, Peter
AU - Supuran, Claudia T.
AU - Carta, Fabrizio
AU - Harrison, David James
AU - Kunkler, Ian H.
AU - Langdon, Simon
N1 - The following organizations are gratefully acknowledged: University of Edinburgh (JM), Medical Research Council (EJJ), EPSRC IMPACT (CW), Medical Research Scotland (CX) and Scottish Universities Life Sciences Alliance (CMP).
This research was financed in part by a Grant of the 7th Framework Program of the European Union (METOXIA project; HEALTH-F2-2009-222741), along with the Breast Cancer Institute (BCI) and Aitken Breast Cancer Research Fund.
PY - 2017
Y1 - 2017
N2 - Hypoxic cancer cells exhibit resistance to many therapies. This study compared the therapeutic effect of targeting the pH regulatory proteins (CAIX, NHE1 and V-ATPase) that permit cancer cells to adapt to hypoxic conditions, using both 2D and 3D culture models. Drugs targeting CAIX, NHE1 and V-ATPase exhibited anti-proliferative effects in MCF-7, MDA-MB-231 and HBL-100 breast cancer cell lines in 2D. Protein and gene expression analysis in 2D showed that CAIX was the most hypoxia-inducible protein of the 3 targets. However, the expression of CAIX differed between the 3 cell lines. This difference in CAIX expression in hypoxia was consistent with a varying activity of FIH-1 between the cell lines. 3D expression analysis demonstrated that both CAIX and NHE1 were up-regulated in the hypoxic areas of multicellular tumor spheroids. However, the induction of CAIX expression in hypoxia was again cell line dependent. 3D invasion assays conducted with spheroids showed that CAIX inhibition significantly reduced the invasion of cells. Finally, the capability of both NHE1 and CAIX inhibitors to combine effectively with irradiation was exhibited in clonogenic assays. Proteomic-mass-spectrometric analysis indicated that CAIX inhibition might be combining with irradiation through stimulating apoptotic cell death. Of the three proteins, CAIX represents the target with the most promise for the treatment of breast cancer.
AB - Hypoxic cancer cells exhibit resistance to many therapies. This study compared the therapeutic effect of targeting the pH regulatory proteins (CAIX, NHE1 and V-ATPase) that permit cancer cells to adapt to hypoxic conditions, using both 2D and 3D culture models. Drugs targeting CAIX, NHE1 and V-ATPase exhibited anti-proliferative effects in MCF-7, MDA-MB-231 and HBL-100 breast cancer cell lines in 2D. Protein and gene expression analysis in 2D showed that CAIX was the most hypoxia-inducible protein of the 3 targets. However, the expression of CAIX differed between the 3 cell lines. This difference in CAIX expression in hypoxia was consistent with a varying activity of FIH-1 between the cell lines. 3D expression analysis demonstrated that both CAIX and NHE1 were up-regulated in the hypoxic areas of multicellular tumor spheroids. However, the induction of CAIX expression in hypoxia was again cell line dependent. 3D invasion assays conducted with spheroids showed that CAIX inhibition significantly reduced the invasion of cells. Finally, the capability of both NHE1 and CAIX inhibitors to combine effectively with irradiation was exhibited in clonogenic assays. Proteomic-mass-spectrometric analysis indicated that CAIX inhibition might be combining with irradiation through stimulating apoptotic cell death. Of the three proteins, CAIX represents the target with the most promise for the treatment of breast cancer.
KW - Carbonic anhydrase IX
KW - NHE1
KW - V-ATPase
KW - Breast cancer
KW - Hypoxia
U2 - 10.18632/oncotarget.17143
DO - 10.18632/oncotarget.17143
M3 - Article
SN - 1949-2553
VL - 8
SP - 42857
EP - 42875
JO - Oncotarget
JF - Oncotarget
IS - 26
ER -
