FADD Signaling in Cancer Cells

癌细胞中的 FADD 信号传导

• 批准号: 8215930
• 负责人: Andrew M Thorburn
• 金额: $ 27.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-22 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215930
• 关键词: Adaptor Signaling Protein; Affect; Agonist; Agreement; Antineoplastic Agents; Apoptosis; Autophagocytosis; Award; Binding Proteins; Biological Response Modifiers; Budgets; Caspase; Cell Death; Cell physiology; Cells; Characteristics; Clinical Trials; Complement; Confusion; DNA Damage; Death Domain; Development; Drug Delivery Systems; Drug usage; Effectiveness; Funding; Genetic; Grant; HMGB1 gene; Histone Deacetylase Inhibitor; Immune; Immune response; Life; Ligands; Malignant Neoplasms; Mediating; Methods; Molecular; Normal Cell; Nutrient; Organelles; Pathway interactions; Period Analysis; Pharmaceutical Preparations; Pharmacologic Substance; Process; Proteins; Receptor Activation; Receptor Signaling; Regulation; Relative (related person); Resistance; Role; Series; Signal Transduction; Specificity; Stimulus; Stress; TNFRSF10A gene; TNFRSF10B gene; TNFRSF6 gene; TNFSF10 gene; Targeted Toxins; Testing; Therapeutic; Therapeutic Agents; Time; Treatment Effectiveness; Tumor Cell Line; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Work; base; cancer cell; cancer therapy; cell killing; cell transformation; deprivation; follow-up; improved; in vivo; inhibition of autophagy; inhibitor/antagonist; insight; interest; killings; mutant; neoplastic cell; novel; pre-clinical; public health relevance; receptor; response; therapeutic target; therapy development; tool; tumor; tumor growth

DESCRIPTION (provided by applicant): Fas Associated Death Domain (FADD) is an adaptor protein that is required for signaling by the Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) receptors. TRAIL receptors are important therapeutic targets in cancer with six TRAIL receptor-targeted drugs in clinical trials at the current time, several others in pre-clinical development and accumulating evidence suggesting that signaling through endogenous TRAIL is important in the mechanism of action of other anti-cancer treatments including DNA damaging agents, anti-metabolites and histone deacetylase inhibitors. The molecular mechanisms by which FADD activates caspases upon TRAIL receptor stimulation are quite well understood, however mechanisms of TRAIL resistance are still poorly understood and this limits our ability to optimally use the TRAIL receptor-targeted drugs. In the previous funding period we analyzed mechanisms of TRAIL resistance and FADD signaling and made the unexpected discovery that TRAIL receptors induce autophagy and that a FADD inhibitor could induce autophagy implying that FADD negatively regulates autophagy. Because autophagy can affect apoptosis responses in tumor cells, we propose that these activities affect the efficiency by which TRAIL receptor signaling activates the apoptosis machinery and thus kills tumor cells. We have also found that autophagy controls the characteristics of dying cells, particularly the release of an immune regulator called HMGB1 and that this also occurs in a FADD-dependent manner in response to TRAIL. Based on these findings, this competitive renewal focuses on three complementary questions: How does FADD regulate autophagy? What effect does autophagy have on TRAIL receptor signaling? And, does manipulation of autophagy provide a way to improve the anti-tumor effect of TRAIL receptor-targeted drugs? To answer these questions we have the following aims. Aim 1. Determine the role of FADD in regulation of autophagy. This aim tests the hypothesis that FADD negatively regulates autophagy by interaction with autophagy regulators. Aim 2. Determine how autophagy affects signaling by TRAIL-R targeted drugs. This aim tests the hypothesis that FADD's ability to inhibit autophagy serves to coordinate competing signals and thus provide fine control over tumor cell death during treatment with TRAIL R-targeted drugs. Aim 3. Test if autophagy manipulation improves the effectiveness of TRAIL-R targeted drugs in vivo. This aim tests the hypothesis that autophagy inhibition will make TRAIL receptor-targeted drugs (lexatumumab, mapatumumab) more effective and uses a unique set of isogenic tumor cells in which we can determine the relative roles of exogenous and endogenous TRAIL receptor stimuli in the anti-tumor response and the role of autophagy in controlling these responses. These studies should provide new insights into FADD and TRAIL receptor signaling, the role of autophagy in determining the response to anti-cancer therapy and provide a basis for improving the use of TRAIL receptor- targeted drugs in treating people with cancer. PUBLIC HEALTH RELEVANCE: In the last few years it has become clear that a hitherto understudied cellular process called autophagy is an important regulator of cancer development and treatment. However there is considerable confusion about what we should try to do to autophagy to improve cancer therapy- in fact it is not clear whether we should try to inhibit autophagy or stimulate it during treatment of cancer. This grant examines signaling by a protein called FADD, which is required for tumor cell killing after activation of TRAIL receptors. This is important because TRAIL receptors are targeted by at least 6 anti-cancer agents and are also important for tumor cell killing by other drugs that work indirectly through TRAIL. In the previous funding period, we made several discoveries; first we found that FADD (and TRAIL) can regulate autophagy. Second, we found that autophagy can modulate the efficiency of tumor cell killing by various drugs including TRAIL. In this proposal we aim to answer the key questions that arose out of the previous work. We will work out how FADD regulates autophagy, how this activity alters signaling by TRAIL receptors and test whether manipulation of these processes alters the effectiveness of treatment by the TRAIL receptor-targeted drugs that are used in people. These studies should provide a way to improve the use of the various anti-cancer agents that target TRAIL receptors which are already in clinical trials and provide a rationale to allow us to manipulate autophagy during cancer treatment.

描述（由申请人提供）：FAS相关的死亡结构域（FADD）是一种衔接蛋白，这是由肿瘤坏死因子因子相关的凋亡诱导配体（TRAIL）受体所必需的。在当前的临床试验中，TRAIL受体是癌症中重要的治疗靶标，在临床试验中具有六个受体受体的药物，在临床前发育领域的其他一些药物和积累的证据表明，通过内源性跟踪信号传导在其他抗癌药物的作用机理中很重要，包括DNA损害剂，抗甲替代物，抗甲替代剂和组酮Deacetlase and Historone deacetlase insimens insys insigant and in ossigation。 FADD激活在跟踪受体刺激时激活胱天蛋白酶的分子机制已得到充分了解，但是耐耐药性的机制仍然很少了解，这限制了我们最佳使用Trail受体靶向药物的能力。在上一个资金期间，我们分析了跟踪阻力和FADD信号传导的机制，并意外发现，径向受体会诱导自噬，而FADD抑制剂可能会诱导自噬，这表明FADD会对自噬进行负调节。由于自噬会影响肿瘤细胞中的凋亡反应，因此我们提出这些活性会影响跟踪受体信号传导激活细胞凋亡机械并因此杀死肿瘤细胞的效率。我们还发现，自噬控制了垂死细胞的特征，尤其是释放称为HMGB1的免疫调节剂，并且这也以FADD依赖性方式出现在响应TRAIL时。基于这些发现，这种竞争性更新着重于三个互补问题：FADD如何调节自噬？自噬对TRAIL受体信号有什么影响？而且，对自噬的操纵是否提供了改善靶向受体靶向药物的抗肿瘤作用的方法？为了回答这些问题，我们有以下目标。目标1。确定FADD在自噬调节中的作用。该目标检验了以下假设，即FADD通过与自噬调节剂相互作用对自噬进行负调节。 AIM 2。确定自噬如何通过TRAIL-R目标药物影响信号传导。这个目的检验了以下假设：FADD抑制自噬的能力可以协调竞争信号，从而在用trail r靶向药物治疗期间对肿瘤细胞死亡进行精细控制。 AIM 3。测试自噬操纵是否可以提高体内TRAIL-R靶向药物的有效性。该目的测试了以下假设：自噬抑制作用将使跟踪受体靶向的药物（Lexatumumab，mapatumumab）更有效，并使用一组独特的异源性肿瘤细胞，在该细胞中，我们可以确定抗肿瘤和内源性跟踪受体刺激在抗肿瘤反应和自动型中的作用中的外源性和内源性轨迹受体刺激的相对作用。这些研究应提供有关FADD和TRAIL受体信号传导的新见解，即自噬在确定对抗癌治疗的反应中的作用，并为改善使用TRAIL受体受体靶向药物在治疗癌症患者中的使用提供了基础。 公共卫生相关性：在过去的几年中，很明显，迄今为止，迄今为止，迄今为止研究的细胞过程称为自噬是癌症发育和治疗的重要调节剂。但是，我们应该尝试为自噬来改善癌症治疗的事情存在很大的困惑 - 实际上，尚不清楚我们是否应该尝试抑制自噬或在癌症治疗期间刺激它。该赠款检查了一种称为FADD的蛋白质的信号传导，该蛋白质是在激活TRAR受体后杀死肿瘤细胞所必需的。这很重要，因为TRAIL受体至少由6种抗癌药物靶向，对于其他通过TRAIL间接起作用的药物杀死肿瘤细胞也很重要。在上一个资金期间，我们发现了一些发现。首先，我们发现FADD（和小径）可以调节自噬。其次，我们发现自噬可以调节包括Trail在内的各种药物杀死肿瘤细胞的效率。在此提案中，我们旨在回答先前工作引起的关键问题。我们将阐明FADD如何调节自噬，这种活动如何改变跟踪受体的信号传导，并测试对这些过程的操纵是否改变了人类使用的Trail受体靶向药物的治疗有效性。这些研究应提供一种方法，以改善针对临床试验中已经进行的TRAIL受体的各种抗癌药物的使用，并提供了一个理由，使我们能够在癌症治疗期间操纵自噬。