Compartmentalized Vacuolar-ATPase-regulated Intracellular Prostate-Specific Antigen (VIP) in Prostate Cancer Cells: Novel findings on the Regulation of the Biomarker

Vacuolar ATPases (V-ATPases) acidify endosomal and lysosomal compartments and contribute to cytosolic and extracellular pH regulation. We studied expression, distribution, and functions of V-ATPases in a cell model of human prostate cancer progression. V-ATPase mRNA V_o subunit isoforms significantly increased as the invasive potential increased from LNCaP (low invasive) to C4-2 and C4-2B (highly invasive). Immunocytochemistry revealed no plasmalemmal V-ATPases regardless of the invasion potential. Primarily endogenous V-ATPases were present that co-localized with endosomal and lysosomal markers. Remarkably, a population of V-ATPases was condensed in a distinct compartment where intracellular Prostate-Specific Antigen (PSA) accumulated and was regulated by V-ATPase: the Vacuolar-ATPase-Regulated Intracellular Prostate-Specific Antigen (VIP) compartment. PSA retention in the VIP compartment was V-ATPase-dependent. Disruption of V-ATPase functions by treatment with bafilomycin A drastically disrupted PSA localization to VIP in LNCaP and C4-2B cells. Bafilomycin A suppressed steady state and androgen-induced PSA expression (mRNA and protein) and secretion in LNCaP cells, indicating that the VIP compartment spatially and functionally coupled V-ATPase and intracellular PSA. In androgen-independent C4-2B cells, PSA expression was also controlled by V-ATPases. We concluded that the primary role of V-ATPase in prostate cancers is not to pump protons out of the cell; yet, a prostate-specific centralized function controlling androgen-dependent and -independent responses involving PSA. The importance of these novel findings is underscored by a prominent co-localization of V-ATPase and PSA in VIP-like structures of epithelial cells at secretory ducts in advanced Grade 4 tumors. Clinical implications, including new and more appropriate ways to use PSA as a predictive/prognostic tool, are discussed.