Abstract
The retinoids, the natural or synthetic derivatives of Vitamin A (retinol), are essential for the normal development of prostate and have been shown to modulate prostate cancer progression in vivo as well as to modulate growth of several prostate cancer cell lines. 9-cis-retinoic acid and all-trans-retinoic acid are the two most important metabolites of retinol. Gap junctions, formed of proteins called connexins, are ensembles of intercellular channels that permit the exchange of small growth regulatory molecules between adjoining cells. Gap junctional communication is instrumental in the control of cell growth. We examined the effect of 9-cis-retinoic acid and all-trans retinoic acid on the formation and degradation of gap junctions as well as on junctional communication in an androgen-responsive prostate cancer cell line, LNCaP, which expressed retrovirally introduced connexin32, a connexin expressed by the luminal cells and well-differentiated cells of prostate tumors. Our results showed that 9-cis-retinoic acid and all-trans retinoic acid enhanced the assembly of connexin32 into gap junctions. Our results further showed that 9-cis-retinoic acid and all-trans-retinoic acid prevented androgen-regulated degradation of gap junctions, post-translationally, independent of androgen receptor mediated signaling. Finally, our findings showed that formation of gap junctions sensitized connexin32-expressing LNCaP cells to the growth modifying effects of 9-cis-retinoic acid, all-trans-retinoic acid and androgens. Thus, the effects of retinoids and androgens on growth and the formation and degradation of gap junctions and their function might be related to their ability to modulate prostate growth and cancer.
Highlights
Retinoids, the natural or synthetic derivatives of vitamin A, regulate embryonic development and organogenesis in adult tissues [1]
Based on the rationale described above and on our experience with other cell lines [26,27], LNCaP-32 cells were treated with 9-Cis-Retinoic Acid (9-CRA) and All trans-retinoic acid (ATRA) for 48 h to examine if they affect Cx32 expression level
We found that both 9-CRA and ATRA had no significant affect on the expression level of adherens junction proteins E-cadherin and a- and b-catenins, the expression level of tight junction associated protein, occludin, was enhanced to some extent (Figure 1D)
Summary
The natural or synthetic derivatives of vitamin A, regulate embryonic development and organogenesis in adult tissues [1]. Retinoid initiated signaling regulates several homeostatic control mechanisms during embryonic development and in adult tissues and one such control mechanism likely to be regulated is the direct cell-cell communication mediated by a special class of cell junctions called gap junctions (GJs) [6,7,8]. To form a GJ cell-cell channel, Cxs first oligomerize as hexamers, called connexons, which dock with the connexons displayed on contiguous cells [10]. Multiple lines of evidence lends credence to the notion that gap junctional communication is an important homeostatic control mechanism for regulating cell growth and differentiation. Impaired Cx expression, or loss of function, has been implicated in the pathogenesis of several types of cancers, and mutations in several Cx genes have been detected in genetic disorders characterized by aberrant cellular proliferation and differentiation [8,10,11,12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
