Abstract
All-trans-retinoic acid and 9-cis-retinoic acid have been reported to have inhibitory effects on pancreatic adenocarcinoma cells and we have shown that this is partly due to induction of apoptosis. In this study, the mechanisms whereby 9-cis-retinoic acid induces apoptosis in these cells were investigated. An involvement of the Bcl-2 family of proteins was shown, such that 9-cis-retinoic acid causes a decrease in the Bcl-2/Bax ratio. Overexpression of Bcl-2 also resulted in inhibition of apoptosis induced by 9-cis-retinoic acid. Furthermore, two broad-range caspase inhibitors blocked DNA fragmentation induced by 9-cis-retinoic acid, but had no effect on viability defined by mitochondrial activity. Using synthetic retinoids, which bind selectively to specific retinoic acid receptor subtypes, we further established that activation of retinoic acid receptor-gamma is essential for induction of apoptosis. Only pan-retinoic acid receptor and retinoic acid receptor-gamma selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-gamma is resistant to the effects of 9-cis-retinoic acid. A retinoic acid receptor-beta/gamma selective antagonist also suppressed the cytotoxic effects of 9-cis-retinoic acid in a dose-dependent manner. This study provides important insight into the mechanisms involved in suppression of pancreatic tumour cell growth by retinoids. Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology*
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Alitretinoin
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Apoptosis / drug effects*
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Aspartic Acid / analogs & derivatives*
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Aspartic Acid / pharmacology
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Cysteine Proteinase Inhibitors / pharmacology
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DNA Fragmentation / drug effects
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Drug Resistance
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Fatty Acids, Unsaturated / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects*
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Genes, bcl-2*
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Humans
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Mice
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Mitochondria / drug effects
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / drug effects
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Neoplasm Proteins / genetics
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / pathology*
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Protein Isoforms / drug effects
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Protein Isoforms / physiology
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Proto-Oncogene Proteins / biosynthesis*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
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Receptors, Retinoic Acid / drug effects*
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Receptors, Retinoic Acid / physiology
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Recombinant Fusion Proteins / physiology
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Retinoic Acid Receptor gamma
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Retinoid X Receptors
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Retinoids / agonists
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Retinoids / antagonists & inhibitors
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Retinoids / pharmacology*
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Transcription Factors / drug effects
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Transcription Factors / physiology
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Transfection
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Tretinoin / pharmacology*
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Tumor Cells, Cultured / drug effects
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bcl-2-Associated X Protein
Substances
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Amino Acid Chloromethyl Ketones
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BAX protein, human
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Bax protein, mouse
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Cysteine Proteinase Inhibitors
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Fatty Acids, Unsaturated
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Neoplasm Proteins
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Protein Isoforms
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Retinoic Acid
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Recombinant Fusion Proteins
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Retinoid X Receptors
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Retinoids
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Transcription Factors
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bcl-2-Associated X Protein
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benzyloxycarbonyl-aspartyl(O-methyl)fluoromethane
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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Alitretinoin
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Aspartic Acid
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Tretinoin
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octa-2,4,6-trienoic acid