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

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.

• Authors: James Meehan, Carol Ward, Arran Turnbull, Jimi Bukowski-Wills, Andrew J Finch, Edward J Jarman, Chrysi Xintaropoulou, Carlos Martinez-Perez, Mark Gray, Matthew Pearson, Peter Mullen, Claudiu T Supuran, Fabrizio Carta, David J Harrison, Ian H Kunkler, Simon P Langdon
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 26 Pg. 42857-42875 (Jun 27 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28476026 (Publication Type: Journal Article)

Chemical References

• Hypoxia-Inducible Factor 1
• SLC9A1 protein, human
• Sodium-Hydrogen Exchanger 1
• Vacuolar Proton-Translocating ATPases
• Carbonic Anhydrase IX
• Oxygen

Topics

• Breast Neoplasms (genetics, metabolism)
• Carbonic Anhydrase IX (antagonists & inhibitors, metabolism)
• Cell Hypoxia
• Cell Line, Tumor
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hydrogen-Ion Concentration
• Hypoxia (genetics, metabolism)
• Hypoxia-Inducible Factor 1 (metabolism)
• Mass Spectrometry
• Oxygen (metabolism)
• Proteomics (methods)
• Sodium-Hydrogen Exchanger 1 (metabolism)
• Vacuolar Proton-Translocating ATPases (metabolism)