Se-methylselenocysteine sensitized TRAIL-mediated apoptosis via down-regulation of Bcl-2 expression.
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.
Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, Jung-Gu, Taegu 700-712, Korea.
Jung Tae
JT
Lee
Tae-Jin
TJ
Lee
Jong-Wook
JW
Park
Taeg Kyu
TK
Kwon
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D003545:Cysteine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019254:Genes, bcl-2; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016566:Organoselenium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017279:Selenocysteine / Q000031:analogs & derivatives; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C474007:Bax protein (53-86); D016566:Organoselenium Compounds; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; D017279:Selenocysteine; D020169:Caspases; D003545:Cysteine; C002979:selenomethylselenocysteine