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Suppression of human prostate cancer cell growth by forced expression of connexin genes
P P Mehta1, C Perez-Stable, M Nadji
1Department of Medicine, University of Miami School of Medicine, Florida, USA.
Abstract:
The cell-to-cell channels in gap junctions, formed of proteins called connexins (Cxs), provide a direct intercellular pathway for the passage of small signaling molecules (< or = 1 kD) between the cytoplasmic interiors of adjoining cells. It has been proposed that alteration in the expression 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 pathogenesis 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. While normal prostate epithelial cells expressed only Cx beta 1, both Cx alpha 1 and Cx beta 1 were detected in PCA cells. The Cxs were localized at the cell-cell contact areas in normal prostate and well-differentiated prostate tumors; however, as 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 alterations with regard to expression of Cx alpha 1 and Cx beta 1 and their assembly into gap junctions during the progression of PCA. Retroviral-mediated transfer of Cx alpha 1 and Cx beta 1 into a Cx-deficient human PCA cell line, LNCaP, inhibited growth, retarded tumorigenicity, and induced differentiation, and these effects were contingent upon the formation of gap junctions. In addition, the capacity to form gap junctions in most Cx-transduced LNCaP cells was lost upon serial passage. Taken together, these findings indicate that the control of proliferation and differentiation of epithelial cells in prostate tumors may depend on the appropriate assembly of Cx beta 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 to form gap junctions.
Insights
Alterations in connexins (Cxs) and gap junction formation are implicated in prostate cancer (PCA) progression. Restoring Cx expression in PCA cells inhibited growth and induced differentiation, suggesting impaired gap junction assembly drives PCA development.
Area of Science:
- Cell Biology
- Oncology
- Molecular Biology
Background:
- Gap junctions, formed by connexins (Cxs), facilitate intercellular communication by allowing passage of small molecules (< or = 1 kD).
- Altered Cx expression and function are hypothesized to contribute to neoplasia initiation.
- Understanding Cx roles in prostate cancer pathogenesis is crucial.
Purpose of the Study:
- To investigate the expression patterns of Cx alpha 1 (Cx43) and Cx beta 1 (Cx32) in normal prostate and prostate tumors.
- To elucidate the role of Cxs and gap junction formation in prostate cancer (PCA) progression.
- To determine the effect of restoring Cx expression on PCA cell behavior.
Main Methods:
- Immunocytochemical analysis of Cx alpha 1 and Cx beta 1 expression in normal prostate and PCA tissues of varying grades.
- Retroviral-mediated gene transfer of Cx alpha 1 and Cx beta 1 into a Cx-deficient human PCA cell line (LNCaP).
- Assessment of cell growth, tumorigenicity, differentiation, and gap junction formation in transduced cells.
Main Results:
- Normal prostate epithelial cells expressed Cx beta 1, while PCA cells showed expression of both Cx alpha 1 and Cx beta 1.
- Cx localization shifted from cell-cell contacts to cytoplasm and was lost in advanced PCA stages.
- Restoration of Cx alpha 1 and Cx beta 1 in LNCaP cells inhibited growth, reduced tumorigenicity, and induced differentiation, contingent on gap junction formation.
Conclusions:
- Prostate tumor progression involves altered expression and assembly of Cx alpha 1 and Cx beta 1 into gap junctions.
- Appropriate assembly of Cx beta 1 and Cx alpha 1 into gap junctions is critical for controlling proliferation and differentiation in prostate tumors.
- PCA development may be linked to the selection of cells with defective gap junction formation capabilities.