title: Inhibitors of vacuolar ATPase proton pumps inhibit human prostate cancer cell invasion and prostate-specific antigen expression and secretion.
abstract: Vacuolar ATPases (V-ATPases) comprise specialized and ubiquitously distributed pumps that acidify intracellular compartments and energize membranes. To gain new insights into the roles of V-ATPases in prostate cancer (PCa), we studied the effects of inhibiting V-ATPase pumps in androgen-dependent (LNCaP) and androgen-independent (C4-2B) cells of a human PCa progression model. Treatment with nanomolar concentrations of the V-ATPase inhibitors bafilomycin A or concanamycin A reduced the in vitro invasion in both cell types by 80%, regardless that V-ATPase was prominent at the plasma membrane of C4-2B cells and only traces were detected in the low-metastatic LNCaP parental cells. In both cell types, intracellular V-ATPase was excessive and co-localized with prostate-specific antigen (PSA) in the Golgi compartment. V-ATPase inhibitors reversibly excluded PSA from the Golgi and led to the accumulation of largely dispersed PSA-loaded vesicles of lysosomal composition. Inhibition of acridine orange staining and transferrin receptor recycling suggested defective endosomal and lysosomal acidification. The inhibitors, additionally, interfered with the AR-PSA axis under conditions that reduced invasion. Bafilomycin A significantly reduced steady-state and R1881-induced PSA mRNA expression and secretion in the LNCaP cells which are androgen-dependent, but not in the C4-2B cells which are androgen ablation-resistant. In the C4-2B cells, an increased susceptibility to V-ATPase inhibitors was detected after longer treatments, as proliferation was reduced and reversibility of bafilomycin-induced responses impaired. These findings make V-ATPases attractive targets against early and advanced PCa tumors.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Vera
authors.initials: V
authors.lastname: Michel
authors.forename: Yamhilette
authors.initials: Y
authors.lastname: Licon-Munoz
authors.forename: Kristina
authors.initials: K
authors.lastname: Trujillo
authors.forename: Marco
authors.initials: M
authors.lastname: Bisoffi
authors.forename: Karlett J
authors.initials: KJ
authors.lastname: Parra
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D011992:Endosomes / Q000187:drug effects; D015870:Gene Expression; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D010641:Phenotype; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055571:Secretory Pathway / Q000187:drug effects; D022142:Secretory Vesicles / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018942:Macrolides; C057620:bafilomycin A; D015741:Metribolone; C036978:concanamycin A; D017430:Prostate-Specific Antigen; D025262:Vacuolar Proton-Translocating ATPases