Role of IkBKe in Stress-Induced Ovarian Cancer Progression

IkBKe 在压力诱发的卵巢癌进展中的作用

• 批准号: 9790897
• 负责人: Claudia B. Colon-Echevarria
• 金额: $ 3.6万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2021-09-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9790897
• 关键词: Address; Adrenergic Agents; Affect; Animals; Anxiety; Anxiety Disorders; Biological Assay; Biology; Cancer Patient; Cancer cell line; Catecholamines; Chronic stress; Clinical; Data; Development; Diagnosis; Disease; Epinephrine; Family; General Population; Genes; Genetic Transcription; Goals; Growth; Infiltration; Inflammation; Inflammatory; Intervention; Lead; Link; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; Mental Depression; Modeling; Molecular; NF-kappa B; NFKB Signaling Pathway; Neoplasm Metastasis; Norepinephrine; Nuclear Translocation; Outcome; Pathway interactions; Patients; Pattern; Phosphorylation; Phosphotransferases; Process; Proteins; Psyche structure; Public Health; Puerto Rico; Quality of life; Regulation; Reporting; Research; Resistance; Role; Sampling; Serine; Signal Transduction; Stress; Survival Rate; Sympathetic Nervous System; Therapeutic Agents; United States; Up-Regulation; Variant; Woman; Zoledronic Acid; advanced disease; adverse outcome; biobehavior; bisphosphonate; cancer cell; cell motility; chronic depression; cytokine; experimental study; female reproductive system; improved; in vitro activity; in vivo; macrophage; member; mortality; mutant; novel; novel therapeutic intervention; novel therapeutics; ovarian neoplasm; overexpression; personalized medicine; prevent; psychologic; psychological distress; psychological stressor; restraint stress; stable cell line; therapeutic target; tumor; tumor growth; tumor microenvironment; tumor progression

Project Summary: Understanding the role of chronic stress in the progression of different diseases, including cancer, has become essential to develop personalized treatments that can improve clinical outcomes. Alterations in mental and psychological states, such as chronic stress, depression and anxiety disorders, may accelerate tumor growth and promote resistance to chemotherapeutic treatments. The consequences of these biobehavioral disorders are prominently seen in ovarian cancer patients, since these women report significant levels of psychological distress. These disorders have been associated with sustained activation of the sympathetic nervous system leading to increased catecholamine levels and inflammation in the tumor microenvironment. Pro-inflammatory pathways, such as the NF-kB signaling pathway, have been linked to ovarian cancer growth and progression. As a long-term goal, this proposal aims to investigate the mechanisms by which chronic stress contributes to ovarian cancer progression. To address this goal, we will investigate the role of IkBKe and the NF-kB signaling pathway in adrenergic-induced ovarian cancer progression. Our central hypothesis states that activation of IkBKe by adrenergic signaling promotes ovarian cancer progression. To answer our hypothesis, specific aim 1 will determine if catecholamine-induced IkBKe activity results in phosphorylation of NF-kB effectors and subsequent transcriptional activity in vitro. We will evaluate phosphorylation patterns and transcription of NF-kB target genes to determine if catecholamines induce IkBKe phosphorylation and resulting NF-kB transcriptional activity. Specific aim 2 will focus on determining if catecholamine-induced IkBKe activation mediates pro-tumoral cellular changes in ovarian cancer. Through functional assays, we will examine the effect of IkBKe activation on ovarian cancer cell invasive potential and inflammatory profile. In addition, we will evaluate IkBKe activation and its correlation with advance disease in ovarian cancer patients. Finally, specific aim 3 will study the requirement of IkBKe activation for ovarian cancer tumor progression in two in vivo orthotopic animal stress models. This contribution will be significant because it will have implications in the treatment of ovarian cancer patients. By generating data that provides the underlying mechanism on how chronic stress can induce cancer progression, novel therapeutic agents and psychological interventions could be developed that could improve quality of life and survival rates across the United States and Puerto Rico.

项目概要： 了解慢性压力在包括癌症在内的不同疾病的进展中的作用已成为 对于开发可以改善临床结果的个性化治疗至关重要。精神和心理上的改变 心理状态，如慢性压力、抑郁和焦虑症，可能会加速肿瘤生长 并促进对化疗的耐药性。这些生物行为障碍的后果 这种情况在卵巢癌患者中尤为常见，因为这些女性报告了显着的心理水平 苦恼。这些疾病与交感神经系统的持续激活有关 导致儿茶酚胺水平升高和肿瘤微环境中的炎症。促炎性 NF-kB 信号通路等信号通路与卵巢癌的生长和进展有关。 作为一个长期目标，该提案旨在研究慢性压力导致的机制 卵巢癌进展。为了实现这一目标，我们将研究 IkBKe 和 NF-kB 信号传导的作用 肾上腺素能诱导的卵巢癌进展的途径。我们的中心假设指出，激活 IkBKe 通过肾上腺素信号传导促进卵巢癌进展。为了回答我们的假设，具体目标 1 将确定儿茶酚胺诱导的 IkBKe 活性是否会导致 NF-kB 效应子的磷酸化和 随后的体外转录活性。我们将评估 NF-kB 的磷酸化模式和转录 靶基因以确定儿茶酚胺是否诱导 IkBKe 磷酸化以及由此产生的 NF-kB 转录 活动。具体目标 2 将重点确定儿茶酚胺诱导的 IkBKe 激活是否介导促肿瘤 卵巢癌的细胞变化。通过功能测定，我们将检查 IkBKe 激活对 卵巢癌细胞的侵袭潜力和炎症特征。此外，我们将评估 IkBKe 激活和 其与卵巢癌患者晚期疾病的相关性。最后，具体目标3将研究需求 在两种体内原位动物应激模型中，IkBKe 激活对卵巢癌肿瘤进展的影响。这 贡献将是巨大的，因为它将对卵巢癌患者的治疗产生影响。经过 生成数据，提供慢性压力如何诱发癌症进展的潜在机制， 可以开发新的治疗药物和心理干预措施来改善生活质量 以及美国和波多黎各的存活率。