Abstract
The Na+/H+ exchanger isoform 1 (NHE1) plays a key role in cytoskeletal anchoring and regulation of intracellular pH, at the leading edge of migrating cells. This distribution and activity of NHE1 in metastatic cancer cells shows a similarity to the localization of the urokinase plasminogen activator receptor (uPAR) resulting in the stimulation of growth factor pathways and degradation of the extracellular matrix. In this study, the mechanism of uPAR activation was examined for its impact in proliferation, stress fiber formation, and tumor growth. Additionally, the amino terminal fragment of uPA (uPA‐ATF) was also used to activate the uPA response. In H1299, uPA increased ERK activation but no significant change occurred in H460 and H358. In the presence of 10 nM uPA or uPA‐ATF, cellular proliferation increased by 20‐30% in H358 and H460, whereas H1299 showed no significant changes. To investigate whether uPAR activation stimulated cell migration, stress fiber formation was measured. All three cell lines showed a significant increase in stress fibers with uPA stimulation which was blocked by inhibition of NHE1. Finally, to determine whether migration and proliferation could combine to support new tumor formation, a soft agar assay was performed. H460 cells showed a significant increase in large tumor formation. Supported by NIH Grant 1R15CA135616‐01, And NSF Grant MCB‐0817784.
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