Abstract
Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional peroxisomal enzyme, hydroxysteroid 17β-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the d-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers.
MeSH terms
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Alkaloids / chemistry
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Alkaloids / pharmacology*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Azocines / chemistry
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Azocines / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Isoflavones / chemical synthesis
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Isoflavones / chemistry
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Isoflavones / pharmacology*
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Molecular Structure
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Peroxisomal Multifunctional Protein-2 / antagonists & inhibitors*
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Peroxisomal Multifunctional Protein-2 / metabolism
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Quinolizines / chemistry
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Quinolizines / pharmacology
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Structure-Activity Relationship
Substances
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Alkaloids
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Antineoplastic Agents
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Azocines
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Enzyme Inhibitors
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Isoflavones
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Quinolizines
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cytisine
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Peroxisomal Multifunctional Protein-2
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HSD17B4 protein, human