6337

SCNN1A

sodium channel, non voltage gated 1 alpha subunit;SCNN1A;sodium channel, non voltage gated 1 alpha subunit

alpha ENaC-2|alpha-ENaC|alpha-NaCH|amiloride-sensitive epithelial sodium channel alpha subunit|amiloride-sensitive sodium channel subunit alpha|amiloride-sensitive sodium channel subunit alpha 2|epithelial Na(+) channel subunit alpha|nasal epithelial sodi

12p13

protein-coding

BACKGROUND: Prostate cancer (PCa) is the second-leading cause of cancer death in American men. This is due largely to the "silent" nature of the disease until it has progressed to a highly metastatic and castrate resistant state. Voltage sensitive sodium channels (VSSCs) are multimeric transmembrane protein complexes comprised of a pore-forming alpha subunit and one or two beta subunits. The beta-subunits modulate surface expression and gating kinetics of the channels but also have inherent cell adhesion molecule (CAM) functions. We hypothesize that PCa cells use VSSC beta-subunits as CAMs during PCa progression and metastasis. METHODS: We overexpressed the beta-2 isoform as a C-terminal fusion protein with enhanced cyan fluorescence protein (ECFP) in the weakly metastatic LNCaP cells. The effect of beta-2 overexpression on cell morphology was examined using confocal microscopy while metastasis-associated behavior was tested by performing several in vitro metastatic functional assays and in vivo subcutaneous tumor studies. RESULTS: We found that cells overexpressing beta-2 (2BECFP) converted to a bipolar fibroblastic morphology. 2BECFP cells were more adhesive than control (ECFP) to vitronectin (twofold) and Matrigel(R) (1.3-fold), more invasive through Matrigel(R) (3.6-fold in 72 hr), and had enhanced migration (2.1-fold in 96 hr) independent of proliferation in wound-healing assays. In contrast, 2BECFP cells have a reduced tumor-take and tumor volume in vivo even though the overexpression of beta-2 was maintained. CONCLUSIONS: Functional overexpression of VSSC beta-subunits in PCa may be one mechanism leading to increased metastatic behavior while decreasing the ability to form localized tumor masses.