Regulation of signaling, in human lung cancer cell lines, that controls cellular proliferation and migration: the effect of lysophosphatidic acid and phenylephrine.

Abstract

One of the hallmarks of cancer is the ability of cells to spread from a tumor of origin to other areas. Metastasis occurs through a coordinated series of events. The Na+‐H+ exchanger (NHE) plays a role in pH regulation and cytoskeletal attachment to the plasma membrane. In this study, we investigated the role of stress fiber formation in cellular migration and tumor formation. To do this, we screened cellular responses to, lysophosphatidic acid (LPA) and phenylephrine (PE) in the presence of absence of the NHE inhibitor, ethyl‐isoproplyamiloride (EIPA) to examine stress fiber formation, cellular proliferation, and tumor formation in three human non‐small lung cancer cell lines. Stimulation with LPA and PE lead to no significant increase in cellular proliferation but lead to an increase in stress by formation in the H460, H358, and H1299 cell lines. Inhibition of NHE by EIPA decreased proliferation by 30‐50% in all cell lines and returned stress fibers formation to basal levels. Using a soft agar assay to examine migration and tumor growth, LPA increased the total number of small tumor formed in H358 and H460 cells. In H358 both PE and LPA increased large tumor formations. These studies indicate that NHE plays a vital role in stress fiber formation and cellular migration and that NHE transport activity is necessary to both functions. Supported by NIH Grant 1R15CA135616‐01 and NSF Grant MCB‐0817784