Inhibition of pH regulation as a therapeutic strategy in hypoxic human breast cancer cells
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James Meehan1, Carol Ward1, Arran Turnbull1, Jimi Bukowski-Wills2, Andrew J. Finch2, Edward J. Jarman1, Chrysi Xintaropoulou1, Carlos Martinez-Perez1, Mark Gray1, Matthew Pearson3, Peter Mullen4, Claudiu T. Supuran5, Fabrizio Carta5, David J. Harrison4, Ian H. Kunkler1 and Simon P. Langdon1
1Cancer Research UK Edinburgh Centre and Division of Pathology Laboratory, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom
2Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom
3IGMM Advanced Imaging Resource, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom
4School of Medicine, University of St Andrews, Fife KY16 9TF, United Kingdom
5Department of Neurofarba, Sez. Chimica Farmaceutica e Nutraceutica, University of Florence, Sesto Fiorentino 50019, Italy
James Meehan, email: [email protected]
Keywords: carbonic anhydrase IX, NHE1, V-ATPase, breast cancer, hypoxia
Received: April 14, 2016 Accepted: March 15, 2017 Published: April 17, 2017
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.
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