Pajak B, Gajkowska B, Orzechowski A
Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw Agricultural University, Warsaw, Poland.
J Physiol Pharmacol. 2005 Jun;56 Suppl 3:119-41.
"Immune escape" is a crucial instrument used by carcinoma cells to overcome numerous strategies of immune system to delete transformed cells. Cellular factors that make cancer cells immune to defence mechanisms are incompletely understood while some remain ambiguous. Up to date evidence points to some proteins and/or signaling molecules that might be a basis for unusual behavior of cancer cells. In particular STAT kinases are currently in the main focus of attention since they were both shown to accelerate and/or to inhibit apoptosis. In our studies we observed that human colorectal COLO 205 cancer cells were resistant to TNF-alpha- or cycloheximide-induced cytotoxicity. However, when TNF-alpha (10 ng/ml) has been given along with cycloheximide (5 micro g/ml, CHX) COLO 205 cells died extensively from apoptosis. Apparently, cycloheximide sensitized cells to TNF-alpha-induced programmed cell death. To investigate the role of STAT-1 alpha in CHX-mediated TNF-alpha-induced COLO 205 cell death certain polyphenolic compounds were studied if they modulate STAT-1 alpha phosphorylation status and STAT-1 alpha-protein interaction at the level of TNF-alpha signalosome in the 6(th), 12(th), and 24(th) hour of experiment. Neither of phenolic compound, namely PI-3K inhibitor (LY294002, 20 microM) nor MEK inhibitor (PD98059, 50 microM), nor flavonol quercetin or kaempferol (10, 100 microM) in contrast to apigenin (20 microM) influenced COLO 205 cell viability during individual or combined treatment with TNF-alpha and CHX. We conclude, that some antiapoptotic proteins were involved but not STAT-1 alpha kinase to resist TNF-alpha-dependent cell death promoting activity. Summing up, except apigenin, the above-mentioned polyphenolic compounds were unable to modulate survival signal in COLO 205 cells initially believed to be suppressed by STAT-1 alpha.
“免疫逃逸”是癌细胞用来对抗免疫系统清除转化细胞的多种策略的关键手段。导致癌细胞对防御机制产生免疫的细胞因子尚未完全明确，有些仍不清晰。目前的证据表明，某些蛋白质和/或信号分子可能是癌细胞异常行为的基础。特别是信号转导和转录激活因子（STAT）激酶目前是主要关注焦点，因为它们既被证明能加速和/或抑制细胞凋亡。在我们的研究中，我们观察到人类结肠癌细胞系COLO 205对肿瘤坏死因子-α（TNF-α）或放线菌酮诱导的细胞毒性具有抗性。然而，当TNF-α（10纳克/毫升）与放线菌酮（5微克/毫升，CHX）同时给予时，COLO 205细胞大量死于凋亡。显然，放线菌酮使细胞对TNF-α诱导的程序性细胞死亡敏感。为了研究STAT-1α在放线菌酮介导的TNF-α诱导的COLO 205细胞死亡中的作用，研究了某些多酚类化合物在实验的第6小时、12小时和24小时是否能调节TNF-α信号体水平上的STAT-1α磷酸化状态和STAT-1α-蛋白质相互作用。与芹菜素（20微摩尔）不同，酚类化合物（即磷脂酰肌醇-3激酶抑制剂（LY294002，20微摩尔）、丝裂原活化蛋白激酶激酶抑制剂（PD98059，50微摩尔）、黄酮醇槲皮素或山奈酚（10、100微摩尔））在与TNF-α和放线菌酮单独或联合处理期间均未影响COLO 205细胞活力。我们得出结论，一些抗凋亡蛋白参与其中，但STAT-1α激酶并未参与抵抗TNF-α依赖性细胞死亡促进活性。总之，除芹菜素外，上述多酚类化合物无法调节最初认为受STAT-1α抑制的COLO 205细胞中的存活信号。
