Abstract
Recent studies establish a critical role of selenium in cancer prevention in vitro and in vivo. Selenium may sensitize TRAIL-mediated apoptosis in human renal cancer cells and increase therapeutic efficacy. In this study, we demonstrate that concomitant administration of TRAIL and Se-methylselenocysteine (Se-MSC) produces synergistic effects on the induction of apoptosis in Caki cells. Se-MSC rapidly and specifically down-regulates expression of the Bcl-2 at transcriptional level. The forced expression of Bcl-2 attenuated Se-MSC plus TRAIL-mediated apoptosis, suggesting that the lessened Bcl-2 expression caused by Se-MSC treatment is critical to the increased sensitivity to TRAIL in renal cancer cells. In addition, we demonstrate that the synergistic effects of Se-MSC and TRAIL result from the activation of the caspase-dependent pathways. Co-administration of HA14-1, a small molecule Bcl-2 inhibitor and TRAIL increased apoptosis in Caki cells. Taken together, Se-MSC-mediated down-regulation of Bcl-2 is able to sensitize Caki cells for TRAIL-induced apoptosis. Thus, selenium-based dietary compounds may help to overcome resistance to TRAIL-mediated apoptosis in renal cancer cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Apoptosis / drug effects*
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Carcinoma / genetics
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Carcinoma / metabolism
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Carcinoma / pathology
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Caspases / metabolism
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Caspases / physiology
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Cysteine / administration & dosage
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Cysteine / analogs & derivatives*
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Cysteine / pharmacology
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Down-Regulation / drug effects
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Drug Evaluation, Preclinical
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Drug Synergism
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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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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / pathology
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Organoselenium Compounds / administration & dosage
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Organoselenium Compounds / pharmacology*
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Peptide Fragments / administration & dosage
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Peptide Fragments / pharmacology
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Proto-Oncogene Proteins / administration & dosage
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Proto-Oncogene Proteins / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Selenocysteine / analogs & derivatives
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TNF-Related Apoptosis-Inducing Ligand / administration & dosage
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
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Tumor Cells, Cultured
Substances
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Bax protein (53-86)
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Organoselenium Compounds
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Peptide Fragments
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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TNF-Related Apoptosis-Inducing Ligand
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Selenocysteine
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Caspases
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Cysteine
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selenomethylselenocysteine