Role of autophagy in tumor cell death

自噬在肿瘤细胞死亡中的作用

• 批准号: 8220991
• 负责人: Andrew M Thorburn
• 金额: $ 40.72万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-19 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220991
• 关键词: Adjuvant; Affect; Aftercare; Antineoplastic Agents; Apoptosis; Autophagocytosis; Behavior; Breast Cancer Cell; Breast Cancer Treatment; Catabolic Process; Cell Death; Cell physiology; Cells; Cessation of life; Characteristics; Clinic; Clinical; Clinical Trials; Confusion; Data; Dendritic Cells; Development; Effectiveness; Genetic; HMGB1 gene; Immune; Immune response; Immune system; Lead; Malignant Neoplasms; Metastatic Neoplasm to the Breast; Methods; Mitochondria; Modeling; Mus; Neoadjuvant Therapy; Nuclear Protein; Nutrient; Outcome; Patients; Pharmaceutical Preparations; Process; Proteins; Recycling; Reporting; Role; Stress; Testing; Toll-like receptors; Treatment Effectiveness; Uncertainty; Vesicle; Work; anticancer research; base; cancer cell; cancer therapy; cell killing; cellular imaging; chemotherapy; deprivation; imaging modality; improved; in vivo; inhibition of autophagy; inhibitor/antagonist; insight; interest; killings; neoplastic cell; novel; public health relevance; research study; response; success; therapy development; toll-like receptor 4; treatment effect; tumor; tumorigenic

DESCRIPTION (provided by applicant): There is great interest in manipulating autophagy to improve cancer treatment but considerable confusion about how to do so. For example, it has become clear in the last few years that many anti-cancer treatments induce autophagy in tumor cells, however, because this autophagy has been reported to both protect and kill tumor cells, even such a basic question as whether we should try to increase or decrease autophagy during cancer treatment is unclear. Despite this uncertainty, clinical trials are being developed that combine autophagy inhibitors with other drugs while other patients are treated with drugs that induce autophagy but without any consideration for how this autophagy affects the outcome. Thus a major need in cancer research is to better understand the roles of autophagy in tumor cell death so that we can decide how best to manipulate autophagy in people with cancer. We recently discovered a previously unrecognized function for autophagy: autophagy controls the selective release of the nuclear protein HMGB1 from dying tumor cells. HMGB1 release from dying tumor cells is known to lead to a beneficial tumor-specific immune response through activation of Toll-like Receptors on dendritic cells but may also induce non-beneficial pro-tumorigenic activities. Therefore, our recent findings open up an entirely new issue that needs to be dealt with as we consider how to manipulate autophagy in people. We hypothesize that it is not just the efficiency of tumor cell killing that is important but that the characteristics of the dying tumor cells, exemplified by selective release of HMGB1, also determines the overall success of treatment. And, we propose that autophagy controls both these processes. To test this hypothesis we will use a well-characterized model of metastatic breast cancer to complete the following aims. Aim 1. Determine how autophagy controls the efficiency and characteristics of tumor cell killing by anti-cancer treatments. This aim will test the hypothesis that autophagy regulates both the efficiency of tumor cell killing and the release of HMGB1 from dying cells but does so differently for different kinds of anti-cancer treatments. Aim 2. Determine which aspects of the autophagic process are required for the different responses during tumor cell death. Autophagy is a dynamic process that involves multiple steps; in this aim, we test the hypothesis that different steps in the process are required for the different functions of autophagy and we use novel single cell imaging methods to determine how autophagy regulates the core apoptosis machinery. Aim 3. Determine how manipulation of autophagy alters the long-term efficacy of cancer treatment in vivo. In this aim, we test the hypothesis that autophagy manipulation can determine the long term effectiveness of breast cancer treatment using a model of adjuvant and neoadjuvant chemotherapy and we will determine which functions of autophagy are important for controlling the response to therapy. These studies will give us new insights into the role of autophagy during tumor cell death and should provide a rationale for developing autophagy manipulation strategies to improve the effectiveness of cancer treatment. 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. Although it is widely believed that autophagy is important during tumor cell death (e.g. after treatment with anti-cancer drugs), the precise roles for autophagy are unclear and it has been reported that autophagy may both protect tumor cells and cause their death under different circumstances. Our lack of understanding of what autophagy does during tumor cell death limits our ability to manipulate autophagy in order to improve cancer treatment. We recently discovered a new function for autophagy during tumor cell killing- autophagy regulates the release of a protein that controls the immune system. We propose that this function along with autophagy's ability to control the amount of tumor cell killing will together determine whether efforts to kill cancer cells are effective or not. The work proposed here will test these ideas and determine how autophagy controls the amount and characteristics of tumor cell death and should provide a framework to attempt to manipulate autophagy in people who are being treated for cancer in order to improve the benefits of the treatment.

描述（由申请人提供）：对操纵自噬来改善癌症治疗的兴趣非常感兴趣，但对如何做到了很大的困惑。例如，在过去的几年中，许多抗癌治疗诱导肿瘤细胞中的自噬，因为据报道这种自噬既可以保护和杀死肿瘤细胞，否则我们是否应该尝试在癌症治疗期间尝试增加或减少自噬。尽管存在这种不确定性，但仍开发出将自噬抑制剂与其他药物相结合的临床试验，而其他患者则接受了诱导自噬的药物治疗，但没有考虑这种自噬如何影响结果。因此，癌症研究的主要需求是更好地了解自噬在肿瘤细胞死亡中的作用，以便我们可以决定如何最好地操纵癌症患者的自噬。我们最近发现了自噬的先前未认识的功能：自噬控制了核蛋白HMGB1从垂死的肿瘤细胞中的选择性释放。已知HMGB1从垂死的肿瘤细胞中释放，通过激活树突状细胞上的Toll样受体来导致有益的肿瘤特异性免疫反应，但也可能诱导非依赖阳光的促肿瘤活性。因此，我们最近的发现开辟了一个全新的问题，需要解决，因为我们考虑如何操纵人们的自噬。我们假设重要的不仅是肿瘤细胞杀伤的效率很重要，而且通过选择性释放HMGB1的特征也决定了治疗的总体成功。而且，我们建议自噬控制这两个过程。为了检验这一假设，我们将使用良好的转移性乳腺癌模型来完成以下目的。目标1。确定自噬如何控制抗癌治疗肿瘤细胞杀死肿瘤细胞的效率和特征。该目标将检验以下假设：自噬调节肿瘤细胞杀伤的效率和HMGB1从垂死细胞中释放，但对于不同种类的抗癌治疗方法，肿瘤却有不同的作用。 AIM 2。确定肿瘤细胞死亡过程中不同反应需要自噬过程的哪些方面。自噬是一个涉及多个步骤的动态过程。在此目标中，我们检验了以下假设：自噬的不同功能需要不同的步骤，并且我们使用新型的单细胞成像方法来确定自噬如何调节核心凋亡机制。目标3。确定自噬的操纵如何改变体内癌症治疗的长期疗效。在此目标中，我们检验了以下假设：自噬操纵可以使用辅助和新辅助化学疗法模型来确定乳腺癌治疗的长期有效性，我们将确定自噬的哪些功能对于控制对治疗的反应很重要。这些研究将使我们对自噬在肿瘤细胞死亡中的作用的新见解，并应为制定自噬操纵策略提供基本原理，以提高癌症治疗的有效性。 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。尽管人们普遍认为自噬在肿瘤细胞死亡中很重要（例如，在用抗癌药物治疗后），但自噬的确切作用尚不清楚，据报道，自噬可能既可以保护肿瘤细胞又在不同情况下造成死亡。我们缺乏对自噬在肿瘤细胞死亡过程中所做的事情的了解限制了我们操纵自噬以改善癌症治疗的能力。我们最近在肿瘤细胞杀伤过程中发现了一种自噬的新功能 - 自噬调节控制免疫系统的蛋白质的释放。我们建议这种功能以及自噬控制肿瘤细胞杀死量的能力将共同确定杀死癌细胞的努力是否有效。这里提出的工作将测试这些想法，并确定自噬如何控制肿瘤细胞死亡的数量和特征，并应提供一个框架，试图操纵正在接受癌症治疗的人的自噬以提高治疗益处。