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Sodium Hydrogen Exchanger 1 and Calcineurin Homologous Protein: A Critical for Survival Mechanism in Non‐Small Cell Lung Cancer

Calcineurin Homologous Protein 1 and 2 (CHP1 and CHP2) are competing cofactors which regulate the exchange activity of the Sodium Hydrogen Exchanger Isoform 1 (NHE1), a transmembrane proton pump vital in maintaining pH homeostasis. Early in tumor development, cancer cells experience an acidic microenvironment and serum deprivation as a result of anaerobic metabolism and poor diffusion of nutrients. To survive, cells must engage regulatory mechanisms to maintain intracellular pH (pHi). NHE1 regulation by CHP1 is required for basal activity, and CHP2 is thought to compete for, and augment this role by an unknown mechanism. CHP2 is also uniquely expressed in malignant tissues but the function of this is unclear. To characterize the roles of NHE1 and CHP2 on pHi in serum starvation, NHE1 and CHP2 RNAi knock down (KD) in H1299 cell lines were generated and serum deprived. NHE1 KD cells showed a decrease in pHi of 0.19 (s=0.02, n=12) and CHP2 KD showed a decrease of 0.23 (s=0.02, n=12). CHP2 KD cells also exhibit an overall lower resting pHi than NHE1 and H1299 wild‐type cell both in serum and serum deprivation. These data suggest that both NHE1 and CHP2 play a significant role in pHi regulation and that the cells are more susceptible to acidification without CHP2 expression. Western blot analysis of cultured cells and human tissues reveals an increase in CHP2 expression in nearly each lung tumor cell line and tissue examined. Real‐time PCR (RT‐PCR) in serum‐deprived conditions measured RNA expression of NHE1, CHP1, and CHP2. Serum deprivation in H1299 lung cells show no significant change in gene expression of either NHE1 (n=3) and CHP1 (n=3) after serum starvation. This supports existing western blot data suggesting that transcriptional regulation of NHE1 and CHP1 does not change under serum deprivation. CHP2 expression in paired diseased and adjacent normal tissue is also examined. By characterizing the mechanism for tumor survival in serum deprivation we can develop new modalities of treatment for Non‐Small Cell Lung Cancer patients.