Sodium butyrate-dependent sensitization of human colon adenocarcinoma COLO 205 cells to TNF-alpha-induced apoptosis.
COLO 205 colon adenocarcinoma cells are highly resistant to extrinsic apoptosis induced by immunomodulatory cytokines. One of the antiapoptotic mechanisms is the expression of cFLIP protein, which inhibits TNF-alpha-induced cell death. The use of metabolic inhibitors, such as sodium butyrate (NaBt), the potent repressor of histone deacetylase, sensitizes tumor cells to TNF-alpha-mediated apoptosis. The Western-blot analysis revealed that in COLO 205 cells the susceptibility to apoptogenic stimuli results from time-dependent reduction in cFLIP(L) protein assembled with DISC complex. At the same time, the level of transmembrane TNF-alpha receptor 1 (TNF-R1) was elevated which is consistent with the exaggerated rate of cell death. Since preincubation of COLO 205 cells with N-acetyl-L-cysteine (NAC), or sodium ascorbate (ASC) did not protect cells from combined NaBt- and TNF-alpha-induced apoptosis, we concluded that deletion of cancer cells is not evoked by oxidative stress. Our results suggest that the combination of TNF-alpha with NaBt targets antiapoptotic protein(s) and may provide efficient and non-toxic treatment of colon cancer.
Pajak
B
B
Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw Agricultural University, Warsaw, Poland. bepaj@wp.pl
Orzechowski
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A
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D006801:Humans; D018384:Oxidative Stress; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002087:Butyrates; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053418:Death Domain Receptor Signaling Adaptor Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha