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Inhibition of pH regulation as a therapeutic strategy in hypoxic human breast cancer cells

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Date
2017
Author
Meehan, James
Ward, Carol
Turnbull, Arran
Bukowski-Wills, Jimi
Finch, Andrew
Jarman, Edward J.
Xintaropoulou, Chrysi
Martinez-Perez, Carlos
Gray, Mark
Pearson, Matthew
Mullen, Peter
Supuran, Claudia T.
Carta, Fabrizio
Harrison, David James
Kunkler, Ian H.
Langdon, Simon
Keywords
Carbonic anhydrase IX
NHE1
V-ATPase
Breast cancer
Hypoxia
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
RM Therapeutics. Pharmacology
NDAS
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Abstract
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.
Citation
Meehan , J , Ward , C , Turnbull , A , Bukowski-Wills , J , Finch , A , Jarman , E J , Xintaropoulou , C , Martinez-Perez , C , Gray , M , Pearson , M , Mullen , P , Supuran , C T , Carta , F , Harrison , D J , Kunkler , I H & Langdon , S 2017 , ' Inhibition of pH regulation as a therapeutic strategy in hypoxic human breast cancer cells ' , Oncotarget , vol. 8 , no. 26 , pp. 42857-42875 . https://doi.org/10.18632/oncotarget.17143
Publication
Oncotarget
Status
Peer reviewed
DOI
https://doi.org/10.18632/oncotarget.17143
ISSN
1949-2553
Type
Journal article
Rights
This is an open access article, licensed under a Creative Commons Attribution 3.0 License (http://creativecommons.org/licenses/by/3.0/)
Description
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.
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/10638

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