Abstract
The hypoxic and serum starved environment of metastasizing cancer cells requires a mechanism to overcome the low intracellular pH induced by the Warburg effect. The sodium hydrogen exchanger isoform 1 (NHE1) is a highly regulated, transmembrane protein that modulates pH of extra and intra cellular environment. One set of proteins which bind and regulate NHE1 include calcineurin homologous proteins 1 and 2 (CHP1&2). CHP1 is necessary for basal NHE1 transport while CHP2, increases the exchange activity and Vmax of NHE1. Both proteins bind to nearly the same NHE1 residues however these interactions are not clearly known. To understand the role that all three proteins may play in regulating cellular function, tissue expressional distribution was conducted on tumor and non‐diseased human tissues. Analysis of RNA sequence from Expression Atlas database revealed that different from published record, CHP2 is expressed within a number non‐diseased tissue including but not limited to: spinal cord, urinary bladder, vagina, tibial nerve, lower leg skin. Analysis of RNA sequence databases of cancerous tissue showed significantly higher expressed CHP2 within a number of, but not all cancer tissues including lung, cervical, and esophogeal cancers. Surprisingly prostate and colorectal adenocarcinoma express CHP2 with a 3–10 fold decrease in expression compared to non‐diseased tissue. To further analyse the expression of CHP2 and NHE1 in lung cancer cells, we performed qPCR on human tissue samples. Cq values displayed a significantly higher expression of CHP2 within squamous cell carcinoma, but not adenocarcinoma, in comparison to adjacent healthy tissue. RNAseq, Expression Atlas, analysis of CHP2 within non‐small cell lung cancer also demonstrates this 15‐fold increased expression for squamous cell carcinoma. This signals an integral role of CHP2 for the survival of cancer cells, and hints at the subsequent impact upon the regulation of NHE1 to allow cells to survive nascent tumour acidification. To examine this possibility, we measured the impact of pHi in several cancer cell lines treated with an NHE1 specific inhibitor or after NHE1 or CHP2 knockdown. This work shows that CHP2 expression is required for cells to maintain sustainable pHi for survival. The impact of NHE1 in hypoxic conditions several tumor cell lines. Thus, the increase in expression and change in transport kinetics demonstrates the effect of CHP2 upon proton transport for NHE1, recovering pHi and increasing cell survival.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Published Version
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