Abstract
Impaired expression of connexins, the gap junction subunits that facilitate direct cell-cell communication, have been implicated in prostate cancer growth. To elucidate the crucial role of connexins in prostate cancer progression, we performed a systematic quantitative RT-PCR screening of connexin expression in four representative prostate cancer cell lines across the spectrum of malignancy. Transcripts of several connexin subunits were detected in all four cell lines, and connexin 43 (Cx43) showed marked elevation at both RNA and protein levels in cells with increased metastatic potential. Analysis of gap-junction-mediated intercellular communication revealed homocellular coupling in PC-3 cells, which had the highest C x 43 expression, with minimal coupling in LNCaP cells where C x 43 expression was very low. Treatment with the gap junction inhibitor carbenoxolone or connexin mimetic peptide ACT-1 did not impair cell growth, suggesting that growth is independent of functional gap junctions. PC-3 cells with C x 43 expression reduced by shRNA showed decreased migration in monolayer wound healing assay, as well as decreased transwell invasion capacities when compared to control cells expressing non-targeting shRNA. These results, together with the correlation between C x 43 expression levels and the metastatic capacity of the cell lines, suggest a role of C x 43 in prostate cancer invasion and metastasis.
Highlights
The factors determining progression and metastasis of solid tumors remain elusive, but exchange of signals and coordinated intercellular communication between different types of cells within the heterogeneous cancer cell population and/or between the cancer cells and their microenvironment are believed to play an important role
We investigated CX43 expression in a mouse model of prostate cancer with spontaneous metastasis generated by orthotopic implantation of MycCaP cells [15]
To verify the connexin 43 (Cx43) expression differences between cell lines at the protein level, we performed Western blot using a polyclonal antibody against Cx43 protein and detected endogenous Cx43 protein expression was elevated in DU145 and Prostate cancer (PC)-3 cells compared with LNCaP and C4-2 cells as expected (Figure 1D)
Summary
The factors determining progression and metastasis of solid tumors remain elusive, but exchange of signals and coordinated intercellular communication between different types of cells within the heterogeneous cancer cell population and/or between the cancer cells and their microenvironment are believed to play an important role. Gap junctions, composed of proteins of the connexin family, are specialized transmembrane channels directly connecting cytoplasm of adjacent cells. Aberrant connexin expression is implicated in developmental www.impactjournals.com/oncotarget abnormalities and multiple cancer types [2], but there has been increasing evidence for GJIC-independent roles of connexins on cell growth, differentiation and tumorigenicity [3]. These findings challenge the traditional view that connexins only function as structural components of gap junctions and suggest their potential roles as signaling molecules
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