Retinoids Regulate the Formation and Degradation of Gap Junctions in Androgen-Responsive Human Prostate Cancer Cells

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.

Kinase programs spatiotemporally regulate gap junction assembly and disassembly: Effects on wound repair

“…These collections of intercellular channels, termed gap junction plaques, permit passage of metabolites of less than approximately 1000 Da between cells while macromolecules are excluded (although small RNAs may pass) [7, 8]. Many cell processes effectively require gap junctionalcommunication including control of cell proliferation, embryonic development, cell differentiation and the coordinated contraction of heart and smooth muscle [2, 3, 9–12].…”

Vitamin D3 Regulates the Formation and Degradation of Gap Junctions in Androgen-Responsive Human Prostate Cancer Cells

“…In subsequent studies, we showed that androgen-regulated formation and degradation of GJs was prevented by 9-CRA and ATRAs [31]. We rationalized that 1-25D might enhance GJ assembly by rescuing the ERAD-targeted pool of Cx32 like 9-CRA and ATRA.…”

“…Our earlier studies showed that Cx32 expression potentiated the growth-inhibitory effect of 9-CRA and ATRA in LNCaP cells [31]. To test if 1-25D has similar effect on growth, we measured cell growth of LNCaP-32 cells at concentrations that were barely growth-inhibitory to LNCaP-P cells.…”

“…Androgens are required to maintain the secretory (differentiation-related) function of the luminal epithelial cells of normal prostate as depletion of androgens by surgical or chemical means triggers apoptosis and/or dedifferentiation of these cells [26]–[29]. Our recent studies have shown that retinoids, which also regulate the proliferation and differentiation of prostate epithelial cells [28], [30], also enhance the assembly of Cx32 into GJs [31]. These studies lend credence to the notion that formation and degradation of GJs may be linked to the proliferation and differentiation of luminal prostate epithelial cells.…”

The Carboxyl Tail of Connexin32 Regulates Gap Junction Assembly in Human Prostate and Pancreatic Cancer Cells

“…Communication Assays-Gap junctional communication was assayed by microinjecting the fluorescent tracers Lucifer yellow (M r 443, lithium salt); Alexa 488 (M r 570, A-10436), or Alexa 594 (M r 760, A-10438) (19,21,23,24). Alexa dyes were purchased from Molecular Probes (Carlsbad, CA), and stock solutions (10 mM) for microinjection were prepared in water.…”