Investigating the role of autophagy in Tak1 null prostate cancer and TRAIL sensitivity

研究自噬在 Tak1 缺失前列腺癌和 TRAIL 敏感性中的作用

• 批准号: 9460624
• 负责人: Megan L Goodall
• 金额: $ 0.03万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9460624
• 关键词: Affect; Apoptosis; Autophagocytosis; CDH1 gene; CHD1 gene; Cancer Etiology; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Chemical Modifier; Chemicals; Chloroquine; Clinical; Complex; Confocal Microscopy; Data; Development; Disease; Disease Outcome; Disease Progression; Disease-Free Survival; Dose; Drug Targeting; Epithelial; Genes; Growth and Development function; Immunoprecipitation; In Vitro; Knockout Mice; Link; LoxP-flanked allele; MAP3K7 gene; Malignant neoplasm of prostate; Modality; Mus; Mutation; Necrosis; Null Lymphocytes; Outcome; Paclitaxel; Pathway interactions; Patient Selection; Patients; Pharmacology; Play; Prostate; Prostatic Neoplasms; Recruitment Activity; Research; Research Proposals; Role; Signal Pathway; Signal Transduction; Starvation; Stress; TNF-related apoptosis-inducing ligand; Testing; Tissue Recombination; Tissues; Tumor Subtype; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; anti-cancer therapeutic; antitumor agent; base; cancer diagnosis; cancer initiation; cancer therapy; clinically relevant; design; experimental study; in vivo; individualized medicine; inhibition of autophagy; inhibitor/antagonist; men; mutant; neoplastic cell; novel; novel therapeutics; protein protein interaction; public health relevance; receptor; response; small hairpin RNA; targeted treatment; therapeutic target; therapy outcome; transcription factor; treatment response; tumor; tumor growth

 DESCRIPTION (provided by applicant) Autophagy is a conserved cell survival pathway that is crucial to proper cell function, yet it is implicated in many diseases including cancer initiation, progression, and response to therapy when altered. Gathering evidence shows that there are certain tumor types characterized by tumor suppressor loss that are highly dependent on autophagy for survival during stress and starvation. The Cramer lab validated MAP3K7/Tak1 as a tumor suppressor gene which is found to be deleted in 30-40% of prostate tumors and is associated with poor disease-free survival. Prostate cancer is the most commonly diagnosed cancer in the United States in men, and the second leading cause of cancer related deaths. Further, the Cramer lab also identified a particularly aggressive subtype of prostate cancer that is characterized by loss of both Tak1 and CHD1. Tak1 has also been shown to activate autophagy, but no direct link between CHD1 and autophagy has been determined. Interestingly, Tak1 loss has been shown to cause a robust cell death response to treatment with TNF-related apoptosis inducing ligand (TRAIL) that is shown in my preliminary data as through necroptosis and NOT canonical apoptosis. Further, my data show that autophagy plays a role in modulating this cell death. It is not fully understood how the loss of Tak1 causes such pronounced cell death when stimulated with TRAIL, and further research into its connection with autophagy is needed. There currently is a small number of genetically targetable mutations in prostate cancer, with little understanding of how common mutations cooperate in the progression of the disease or therapy outcome. Identification and understanding of targetable signaling pathways that are needed for survival, such as Tak1 with autophagy, will allow for more appropriate and direct therapies. Furthermore, identifying the role of coordinate loss of Tak1 and CHD1 in regard to aggressive prostate cancer will allow us to elucidate their role in altering autophagic flux and enable tailored treatments. The mechanism of how autophagy regulates cell death through necroptosis with loss of Tak1 and how Tak1 cells are sensitized to TRAIL will be evaluated in this proposal and could explain a previously unknown connection between pathways leading to targetable therapeutics. In this research proposal, I intend to examine the role of Tak1 loss on autophagy and how it relates to TRAIL sensitivity. I will use tissue recombination to determine how altered autophagy in Tak1 cells, in the context of CHD1 loss, modifies prostate cancer development, progression, and treatment response. Using shRNA, sgRNA, and chemical modifiers of autophagy, I will sensitize Tak1 null mouse prostate cells to anti- cancer therapies, specifically TRAIL. If sensitization of Tak1 null cells to TRAIL is achieved in vivo with autophagy inhibitors, it will demonstrate Tak1 as a selectable marker in prostate cancer. Thus, if successful, patients with the subtype of prostate cancers containing Tak1 and CHD1 loss would have targeted treatment options, TRAIL and autophagy inhibitors, increasing results in those who would benefit and avoiding unnecessary and potentially harmful treatments for those who would not.

 描述（由申请人提供）自噬是一种保守的细胞存活途径，其对适当的细胞功能至关重要，但它涉及许多疾病，包括癌症的发生， 进展和改变时对治疗的反应。越来越多的证据表明，某些肿瘤类型的特征是肿瘤抑制因子的丢失，这些肿瘤在应激和饥饿期间高度依赖于自噬来生存。Cramer实验室验证了MAP 3 K7/Tak 1是一种肿瘤抑制基因，该基因在30-40%的前列腺肿瘤中缺失，与无病生存率低相关。前列腺癌是美国男性中最常见的诊断癌症，也是癌症相关死亡的第二大原因。此外，Cramer实验室还确定了一种特别具有侵袭性的前列腺癌亚型，其特征是Tak 1和CHD 1的丢失。Tak 1也被证明可以激活自噬，但CHD 1和自噬之间没有直接联系。有趣的是，Tak 1丢失已被证明会导致对TNF相关凋亡诱导配体（TRAIL）治疗的强烈细胞死亡反应，这在我的初步数据中显示为通过坏死性凋亡而不是典型的凋亡。此外，我的数据表明，自噬在调节这种细胞死亡中起作用。目前还不完全清楚Tak 1的缺失如何在TRAIL刺激下导致如此明显的细胞死亡，需要进一步研究其与自噬的联系。 目前在前列腺癌中存在少量遗传靶向突变，对常见突变如何在疾病进展或治疗结果中合作知之甚少。识别和理解生存所需的靶向信号通路，如Tak 1与自噬，将允许更适当和直接的治疗。此外，确定Tak 1和CHD 1在侵袭性前列腺癌中的协调丢失的作用将使我们能够阐明它们在改变自噬通量中的作用， 实现个性化治疗。自噬如何通过坏死性凋亡与Tak 1的丢失来调节细胞死亡以及Tak 1细胞如何对TRAIL敏感的机制将在本提案中进行评估，并可以解释导致靶向治疗的途径之间先前未知的联系。 在这项研究计划中，我打算研究Tak 1丢失对自噬的作用以及它与TRAIL敏感性的关系。我将使用组织重组来确定在CHD 1丢失的背景下，Tak 1细胞中改变的自噬如何改变前列腺癌的发展，进展和治疗反应。使用shRNA、sgRNA和自噬的化学修饰剂，我将使Tak 1缺失的小鼠前列腺细胞对抗癌疗法，特别是TRAIL敏感。如果Tak 1缺失细胞对TRAIL的致敏在体内通过自噬实现， 抑制剂，它将证明Tak 1作为前列腺癌的选择性标记。因此，如果成功的话，患有包含Tak 1和CHD 1损失的前列腺癌亚型的患者将有针对性的治疗选择，TRAIL和自噬抑制剂，增加那些受益者的结果，并避免对那些不受益者进行不必要和潜在有害的治疗。