Suppression of human prostate cancer cell growth by forced expression of connexin genes

The cell-to-cell channels in gap junctions, formed of proteins called conne xins (Cxs), provide a direct intercellular pathway for the passage of small signaling molecules (less than or equal to 1 kD) between the cytoplasmic i nteriors of adjoining cells. It has been proposed that alteration in the ex pression and function of Cxs may be one of the genetic changes involved in the initiation of neoplasia. To elucidate the role of Cxs in the pathogenes is of human prostate cancer (PCA), the pattern of expression of Cx alpha(1) (Cx43) and Cx beta(1) (Cx32) was studied by immunocytochemical analysis in normal prostate and in prostate tumors of different histological grades. W hile normal prostate epithelial cells expressed both Cx alpha(1) and Cx bet a(1) were detected in PCA The Cxs were localized a; the cell-cell contact a reas in normal prostate and well-differentiated prostate tumors; however, a s prostate tumors progressed to more undifferentiated stages, the Cxs were localized in the cytoplasm, followed by an eventual loss in advanced stages . Thus, epithelial cells from prostate tumors showed subtle and gross alter ations with regard to expression of Cx alpha(1) and Cx beta(1) and their as sembly into gap junctions during the progression of PCA. Retroviral-mediate d transfer of Cx alpha(1) and Cx beta(1) into a Cx-deficient human PCA cell line, LNCaP, inhibited growth, retarded tumorigenicity, and induced differ entiation, and these effects were contingent upon the formation of gap junc tions. in addition, the capacity to form gap junctions in most Cx-transduce d LNCaP cells was lost upon serial passage. Taken together, these findings indicate that the control of proliferation and differentiation of epithelia l cells in prostate tumors may depend on the appropriate assembly of Cx bet a(1) and Cx alpha(1) into gap junctions and that the development of PCA may involve the positive selection of cells with an impaired ability io form g ap junctions. Published 1999 Wiley-Liss, Inc.