Regulation of cell motility by Na+/H+ exchanger NHE1: implications for cancer development

Abstract

Essential roles of ion channels and transporters in regulation of cell motility have been discovered within the last decade. Here, I review recent evidence from our laboratory and others regarding the roles of the Na+/H+ exchanger NHE1 in cell motility, with particular focus on the implications for cancer metastasis. In many cell types, NHE1 localizes to the leading edge of migrating cells and regulates directional cell motility by mechanisms which include the formation of intra‐ and extracellular pH‐gradients and likely also direct protein‐protein interactions and local cell volume changes. In addition, NHE1 localizes strongly to invadopodia: actin‐rich structures assigned essential roles in invading cells. Here, NHE1 appears to be involved in both invadopodia formation and in their extracellular matrix‐degrading function. NHE1 is upregulated in a wide range of human cancers, and inhibition/knockdown of NHE1 attenuates metastasis in several cancer models. However, under some conditions, NHE1 inhibition/knockdown increases adhesiveness and motility, suggesting that the specific role of NHE1 is context‐dependent. In conclusion, NHE1 plays important roles in controlling cell motility. However, to exploit the obvious potential of interfering with NHE1 function to treat cancer metastasis, greater mechanistic understanding of the mechanisms is needed.Funding: Danish Cancer Society, Danish Research Council