Abstract
During carcinogenesis, pancreatic acinar cells can dedifferentiate into ductal adenocarcinoma of the pancreas. DSL-6A/C1 cells represent an in vitro model of this carcinogenic sequence. This study was designed to examine the effects of retinoids on cell growth in DSL-6A/C1 cells and to characterize further the molecular mechanisms underlying the antiproliferative actions of retinoids. Treatment of DSL-6A/C1 cells with retinoids results in a time- and dose-dependent inhibition of cell growth, paralleled by a retinoid-mediated transactivation of a pTK::betaRAREx2-luciferase reporter construct transiently transfected into DSL-6A/C1 cells. Retinoid receptor expression was evaluated by reverse transcriptase polymerase chain reaction (RT-PCR) using subtype-specific primers and demonstrated expression of retinoic acid receptor alpha (RAR-alpha), RAR-beta and retinoid X receptor alpha (RXR-alpha). Using a panel of receptor subtype-specific agonists, the RAR-alpha specific agonist Ro 40-6055 was the most potent retinoid in terms of growth inhibition. Furthermore, all-trans-retinoic acid-mediated growth inhibition and transactivation was completely blocked by the RAR-alpha-specific antagonist Ro 41-5253. In summary, the RAR-alpha subtype predominantly mediates the antiproliferative effects of retinoids in DSL-6A/C1 cells. Furthermore, this cell system provides a feasible tool to study the molecular mechanisms underlying the growth inhibitory effects of retinoids in ductal pancreatic carcinoma cells derived from a primary acinar cell phenotype.
Highlights
To verify the ductal phenotype of DSL-6A/Cl cells, we initially examined the expression of cell type-specific markers in two wellcharacterized pancreatic carcinoma cell lines, AR42J and Dan-G, and compared them with DSL-6A/Cl cells
As an initial attempt to determine the responsiveness of a dedifferentiated pancreatic acinar cell line to the antiproliferative effects of retinoids, we examined the effects of the naturally occurring retinoid all-trans-retinoic acid (ATRA) on anchorage-dependent growth in DSL-6A/C cells
Similar effects could be observed when we investigated ATRA-mediated transactivation of the pTK::4RAREx2-luc reporter construct in transiently transfected DSL-6A/C 1 cells: incubation with 1O,M retinoic acid receptors (RAR)-aspecific antagonist Ro 41-5253 completely blocks the stimulation of luciferase activity induced by 100 nM ATRA (Figure 7 B)
Summary
The aim of our study was to establish this cell line as a suitable in vitro model to investigate the molecular mechanisms involved in retinoidmediated growth inhibition
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