Roles of the Na+/H+ Exchanger Isoform 1 and Urokinase in Prostate Cancer Cell Migration and Invasion.

Abstract	Prostate cancer is a leading cause of cancer-associated deaths in men over 60 years of age. Most patients are killed by tumor metastasis. Recent evidence has implicated a role of the tumor microenvironment and urokinase plasminogen activator (uPA) in cancer cell migration, invasion, and metastasis. Here, we examine the role of the Na+/H+ exchanger isoform 1 (NHE1) and uPA in DU 145 prostate cancer cell migration and colony formation. Knockout of NHE1 reduced cell migration. The effects of a series of novel NHE1/uPA hexamethylene-amiloride-based inhibitors with varying efficacy towards NHE1 and uPA were examined on prostate cancer cells. Inhibition of NHE1-alone, or with inhibitors combining NHE1 or uPA inhibition-generally did not prevent prostate cancer cell migration. However, uPA inhibition-but not NHE1 inhibition-prevented anchorage-dependent colony formation. Application of inhibitors at concentrations that only saturate uPA inhibition decreased tumor invasion in vivo. The results suggest that while knockout of NHE1 affects cell migration, these effects are not due to NHE1-dependent proton translocation. Additionally, while neither NHE1 nor uPA activity was critical in cell migration, only uPA activity appeared to be critical in anchorage-dependent colony formation of DU 145 prostate cancer cells and invasion in vivo.
Authors	Xiuju Li, Benjamin Buckley, Konstantin Stoletov, Yang Jing, Marie Ranson, John D Lewis, Mike Kelso, Larry Fliegel
Journal	International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 24 (Dec 09 2021) ISSN: 1422-0067 [Electronic] Switzerland
PMID	34948058 (Publication Type: Journal Article)
Chemical References	Membrane Proteins PLAU protein, human SLC9A1 protein, human Sodium-Hydrogen Exchanger 1
Topics	Cell Line, Tumor Cell Movement Cell Proliferation Disease Progression Gene Expression Regulation, Neoplastic Gene Knockout Techniques Humans Male Membrane Proteins (metabolism) Prostatic Neoplasms (genetics, metabolism) Sodium-Hydrogen Exchanger 1 (genetics, metabolism) Tumor Microenvironment Up-Regulation

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