IFN-alpha competes with TNF-alpha for STAT-1alpha; molecular basis for immune escape of human colon adenocarcinoma COLO 205 cells.
The resistance of transformed colon epithelial cells to immune system-mediated extrinsic apoptosis allows the development of fast growing colon cancer. Several tactics have been shown to clarify how colon adenocarcinomas avoid cell deletion and remain viable. Regardless of the presence of active membrane receptors, colorectal cancer cells resist interferon-mediated cell death. Similarly, they are refractory to TNF-alpha-dependent apoptosis. In our studies, we assumed that IFN-R and TNF-R1 receptors compete for STAT-1alpha kinase. Western blot and immunoprecipitation analyses were used to evaluate the protein to protein interactions. Cell viability was measured by MTT assay. We observed that STAT-1alpha kinase is bound to TRADD protein in TNF-R1 signalosome irrespective of the TNF-R1 bound ligand. The amount of STAT-1alpha kinase associated with TRADD was diminished after pretreatment with IFNs. IFN-alpha stimulated the survival of COLO 205 cells rather than promoted cell death. The latter was accompanied by NF-kappaB activation, a fact known to promote anti-apoptosis. STAT-1alpha renders colon adenocarcinoma COLO 205 cells less susceptible to TNF-alpha-induced apoptosis but IFN-alpha further extends the immune escape.
Pajak
Beata
B
Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw Agricultural University, 02-776 Warsaw, Poland.
Orzechowski
Arkadiusz
A
D000230:Adenocarcinoma / Q000188:drug therapy*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D016898:Interferon-alpha / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*