The Role of CD95 as a Tumor Promoter

CD95 作为肿瘤启动子的作用

• 批准号: 7122337
• 负责人: Marcus E. Peter
• 金额: $ 29.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-16 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122337
• 关键词: CD95 molecule; MCF7 cell; biological signal transduction; breast neoplasms; clinical research; drug adverse effect; drug related neoplasm /cancer; enzyme linked immunosorbent assay; flow cytometry; gel mobility shift assay; gene expression; gene induction /repression; genetic regulation; human tissue; laboratory mouse; neoplasm /cancer genetics; neoplasm /cancer invasiveness; nuclear factor kappa beta; ovary neoplasms; point mutation; polymerase chain reaction; receptor expression; small interfering RNA; tumor promoters; urokinase; western blottings

DESCRIPTION (provided by applicant): The death receptor CD95 (APO-I/Fas) is best known for its apoptosis inducing activity which involves recruitment of the adaptor molecule FADD and initiator caspases to the intracellular death domain of the receptor. Despite its apoptotic potential most human tumors are refractory to the cytotoxic effects of CD95 ligand. This is due either to upregulation of antiapoptotic genes, functional elimination of CD95 apoptosis signaling pathway components, mutation or downregulation of CD95. In contrast, CD95 ligand (CD95L) levels are elevated in many cancer patients and in patients receiving chemotherapy, either systemically in the serum or within the tumor itself. This has mainly been viewed as an immune escape mechanism to eliminate infiltrating lymphocytes. We recently found that CD95L induces increased motility and invasiveness in multiple apoptosis resistant tumor cells. Engagement of CD95 triggered activation of multiple signaling pathways, 3 of which - activation of NF-kappaB, Erkl/2 and caspase-8 - were found to contribute to this novel activity of CD95. We also reported that the expression of a combination of wild-type and mutant CD95, a situation frequently found in human tumors carrying a heterozygous mutation in the death domain of CD95, completely blocks apoptosis signaling but allows full activation of nonapoptotic pathways. We hypothesize that CD95 on apoptosis resistant tumor cells functions as a tumor promoting receptor and that acquiring a point mutation in one allele of CD95 converts the tumor suppressor CD95 into a tumor promotor. Furthermore we hypothesize that increased concentrations of CD95L found in cancer patients can contribute to increased tumorigenicity of tumors. To test these hypotheses in vitro and in vivo we propose the following three specific aims: Specific Aim 1: Determine the mechanism by which CD95 induces tumorigenic pathways. Specific Aim 2: Identify and characterize the CD95 induced genes that regulate CD95's tumor promoting activities. Specific Aim 3: Test whether chemotherapeutic drugs can induce invasiveness of drug resistant tumor cells. Our studies may provide the means to counteract the novel tumorigenic activities of CD95 by either blocking the activity of CD95L, the tumorigenic signaling pathways, or the tumorigenic genes activated in response to CD95 stimulation.

描述（由申请人提供）：死亡受体CD95（apo-i/fas）以其凋亡诱导活性而闻名，涉及适配器分子FADD和引发剂caspase募集到受体的细胞内死亡结构域。尽管有凋亡的潜力，大多数人类肿瘤对CD95配体的细胞毒性作用产生了难治性。这要么是由于抗凋亡基因的上调，CD95凋亡信号通路成分的功能消除，CD95的突变或下调。相比之下，许多癌症患者以及接受化疗的患者（在血清中或肿瘤本身内接受化学疗法）的CD95配体（CD95L）水平升高。这主要被视为消除浸润淋巴细胞的免疫逃生机制。我们最近发现，CD95L诱导多种抗凋亡肿瘤细胞的运动性和侵袭性提高。 CD95的参与触发了多个信号通路的激活，其中3个 - NF -kappab，Erkl/2和caspase -8的激活可有助于CD95的这种新活性。我们还报道说，野生型和突变体CD95的结合是在CD95死亡结构域中携带杂合突变的人类肿瘤中经常发现的情况，完全阻止了凋亡信号传导，但允许完全激活非凋亡途径。我们假设抗凋亡肿瘤细胞上的CD95充当促进受体的肿瘤，并且在一个CD95等位基因中获得点突变会将肿瘤抑制CD95转化为肿瘤启动子。此外，我们假设在癌症患者中发现的CD95L浓度增加可能有助于增加肿瘤的肿瘤性。为了在体外和体内检验这些假设，我们提出以下三个特定目的：特定目标1：确定CD95诱导肿瘤途径的机制。特定目标2：确定并表征调节CD95促进活性的CD95诱导基因。特定目标3：测试化学治疗药物是否可以诱导耐药性肿瘤细胞的侵入性。我们的研究可以通过阻止CD95L的活性，致瘤信号通路或因CD95刺激而激活的致瘤基因来抵消CD95的新型致癌活性的手段。