MECHANISMS OF TGE-B RESISTANCE IN COLON CARCINOMA CELLS

转化生长因子-β可能在结肠癌的治疗中取得成功 因为它能抑制反应性人结肠癌的增殖 细胞，并引起类似分化的效应。然而，大约50% 被测试的结肠癌细胞对转化生长因子-β无反应。整体而言 这项提议的目标是扩大以前建立的模式系统 用于人结肠癌细胞对转化生长因子-β的耐药性，并利用这一点 用于识别转化生长因子-β可能机制的模型系统 抵抗。从这项提案中获得的结果将确定目标 用于药物的开发，这些药物要么能模拟抑制作用 转化生长因子-β在上皮性结肠肿瘤中的作用或将消除 转化生长因子-β对生长调节的抵抗力。范围： 旨在阐明和/或其作用机制的调查 对转化生长因子-β的抵抗包括：(1)受体结合的特征 以及抗性和敏感克隆中的受体亚型，(2) G蛋白和ras基因受累或改变的研究 癌蛋白在转化生长因子-β(G)产生的细胞信号转导中的作用 蛋白质似乎参与转化生长因子-β诱导的细胞有丝分裂 成纤维细胞)，以及(3)调节变化的研究 原癌基因c-myc、c-fos和c-jun(和 它们的蛋白质产物)来识别这些分子中的任何变化 信号转导和转录调控之间的联系。上一首 研究表明，最初鉴定出的抗转化生长因子β的克隆中有3/4 C-myc过度表达，已被证明改变转化生长因子-β 在其他细胞中的反应性。 其他实验将集中在蜂窝环境作为一种 转化生长因子-β反应性改变的介体。生产过剩，或 对生长刺激性自分泌因子的反应性 克隆可能会超过转化生长因子-β的任何潜在抑制作用。 因此，表皮生长因子、转化生长因子-α及其受体参与转化生长因子-β 阻力将得到解决。

TGF-beta may potentially be successful in the treatment of colon cancer since it inhibits the proliferation of responsive human colon carcinoma cells and elicits differentiation-like effects. However, approximately 50% of colon carcinoma cells tested were unresponsive to TGF-beta. The overall goal of this proposal is to expand a previously-established model system for TGF-beta resistance in human colon carcinoma cells, and to utilize this model system to identify possible mechanisms underlying TGF-beta resistance. The result obtained from this proposal will identify targets for the development of drugs which will either mimic the inhibitory effects of TGF-beta on epithelial colon tumors or which will eliminate the development of resistance to growth regulation by TGF-beta. Areas of investigation aimed at elucidating mechanisms of action of and/or of resistance to TGF-beta include: (1) Characterization of receptor binding and receptor subtypes in the resistant and sensitive clones, (2) Investigation of the involvement or alteration of G proteins and of ras oncoproteins in transduction of cellular signals generated by TGF-beta (G proteins appear to be involved in TGF-beta-induced mitogenesis in fibroblast cells), and (3) Investigation of alterations in the regulation of expression of the nuclear proto-oncogenes c-myc, c-fos, and c-jun (and their protein products) to identify any alterations in these molecular links between signal transduction and transcriptional regulation. Previous work indicated that 3/4 of initially-identified TGF-Beta-resistant clones over-expressed c-myc, an event which has been shown to alter TGF-Beta responsiveness in other cells. Additional experiments will be focused on the cellular environment as a mediator of altered TGF-beta responsiveness. Overproduction of, or responsiveness to, growth stimulatory autocrine factors in the resistant clones may outweigh any potential inhibitory effects of TGF-beta. Therefore, involvement of EGF, TGF-alpha and the EGF receptor in TGF-beta resistance will be addressed.