title: Intercellular communication and human prostate carcinogenesis.
abstract: Gap-junction-mediated intercellular communication (GJIC) is required for completion of embryonic development, tissue homeostasis, and regulation of cell proliferation and death. Although, as emphasized in several reports, defects or disruption of GJIC may be important in carcinogenesis, the potential role of GJIC in the onset and progression of human prostate cancer remains ill-defined. The gap junction channel-forming connexins (Cx) comprise a multigene family of highly conserved proteins that are differentially expressed in a tissue- and development-specific manner; changes in connexin expression are also commonly seen during cellular differentiation. However, when multiple connexins are concurrently expressed, gap junction channels may consist of more than one connexin species. This is important, because only certain pairings give rise to functional channels. In our studies, we investigated GJIC in a panel of both nontumorigenic (RWPE-1) and malignant (RWPE-2, LNCaP, DU-145) human prostate epithelial cells, compared to a normal rat liver epithelial F344 (WB-1) cell line, as it was found to be junctionally proficient. In addition, expression and regulation of Cx43 and Cx32 were also inspected using western blot analysis. The ability of hormones, antihormones, and the antihypertensive drug forskolin to restore GJIC in nontumorigenic and malignant human prostate epithelial cells was examined by the scrape-loading/dye transfer (SL/DT) or fluorescence recovery after photobleaching (FRAP) methods using an Ultima laser cytometer. Results from both assays showed that neither nontumorigenic nor malignant prostate cells have functional GJIC. However, both estrone (E1) and forskolin (FK) induced a significant increase (4.4- and 2.8-fold, respectively) in cell-cell communication only in the RWPE-1 cells. Interestingly, the use of Matrigel, a solubilized basement membrane, as substrate for cell attachment and growth resulted in the rescue of GJIC activity in RWPE-1 cells, as revealed by the SL/DT method. Furthermore, E1 induced a twofold increase in connexin 43 (Cx43), whereas forskolin caused a 50% reduction in Cx32 expression in RWPE-1 cells. These data suggest that agents that increase Cx43:Cx32 ratio may restore GJIC in junctionally deficient cells, providing a basis for the development of new strategies for the prevention and treatment of human prostate cancer.
authors.affiliation: Department of Experimental Oncology and Clinical Application, University Medical School, Palermo, Italy. lucashbl@unipa.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Carruba
authors.forename: Rosalba
authors.initials: R
authors.lastname: Stefano
authors.forename: Letizia
authors.initials: L
authors.lastname: Cocciadiferro
authors.forename: Francesca
authors.initials: F
authors.lastname: Saladino
authors.forename: Antonietta
authors.initials: A
authors.lastname: Di Cristina
authors.forename: Erik
authors.initials: E
authors.lastname: Tokar
authors.forename: Salmann T A
authors.initials: ST
authors.lastname: Quader
authors.forename: Mukta M
authors.initials: MM
authors.lastname: Webber
authors.forename: Luigi
authors.initials: L
authors.lastname: Castagnetta
mesh_terms: D015197:Carcinogenicity Tests; D002450:Cell Communication / Q000502:physiology*; D002454:Cell Differentiation; D002455:Cell Division; D003094:Collagen; D017630:Connexins / Q000502:physiology; D004338:Drug Combinations; D004847:Epithelial Cells / Q000473:pathology; D017629:Gap Junctions / Q000502:physiology*; D006801:Humans; D007797:Laminin; D008297:Male; D011471:Prostatic Neoplasms / Q000209:etiology / Q000473:pathology*; D011509:Proteoglycans
chemical_list: D017630:Connexins; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen