Abstract
1α-25(OH)2 vitamin D3 (1-25D), an active hormonal form of Vitamin D3, is a well-known chemopreventive and pro-differentiating agent. It has been shown to inhibit the growth of several prostate cancer cell lines. Gap junctions, formed of proteins called connexins (Cx), are ensembles of cell-cell channels, which permit the exchange of small growth regulatory molecules between adjoining cells. Cell-cell communication mediated by gap junctional channels is an important homeostatic control mechanism for regulating cell growth and differentiation. We have investigated the effect of 1-25D on the formation and degradation of gap junctions in an androgen-responsive prostate cancer cell line, LNCaP, which expresses retrovirally-introduced Cx32. Connexin32 is expressed by the luminal and well-differentiated cells of normal prostate and prostate tumors. Our results document that 1-25D enhances the expression of Cx32 and its subsequent assembly into gap junctions. Our results further show that 1-25D prevents androgen-regulated degradation of Cx32, post-translationally, independent of androgen receptor (AR)-mediated signaling. Finally, our findings document that formation of gap junctions sensitizes Cx32-expressing LNCaP cells to the growth inhibitory effects of 1-25D and alters their morphology. These findings suggest that the growth-inhibitory effects of 1-25D in LNCaP cells may be related to its ability to modulate the assembly of Cx32 into gap junctions.
Highlights
The role of Vitamin D3, and its active hormonal form 1a25(OH)2 vitamin D3 (1-25D), as an anti-neoplastic, pro-differentiating, and pro-apoptotic agent has been established in a wide variety of normal and malignant epithelial cells, including prostate cancer (PCA) [1,2,3,4]
Our subsequent studies showed that androgen-regulated degradation of Cx32 was abrogated by all-trans retinoic acid (ATRA) and 9-Cis retinoic acid (9-CRA) [31]
We found that Gap junction (GJ) were not formed when cells were treated with Casodex in normal serum or in androgen-depleted medium containing MB as was observed in our earlier studies (Figure 7) [25,31]
Summary
The role of Vitamin D3, and its active hormonal form 1a25(OH) vitamin D3 (1-25D), as an anti-neoplastic, pro-differentiating, and pro-apoptotic agent has been established in a wide variety of normal and malignant epithelial cells, including prostate cancer (PCA) [1,2,3,4]. The actions of 1-25D are mediated by binding to vitamin D receptor, one of the members of nuclear receptor superfamily, which is expressed in a wide variety of cells, including prostate. To form a GJ cell-cell channel, Cxs first oligomerize in the endoplasmic reticulum or the trans-Golgi network as a hexamer, called connexon, which docks with the connexon displayed on a contiguous cell [13,14]. Mutations in several Cx genes have been detected in genetic disorders characterized by aberrant cellular proliferation and differentiation [13,20]
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