Role of IkBKe in Stress-Induced Ovarian Cancer Progression

项目总结： 了解慢性压力在包括癌症在内的不同疾病进展中的作用已经成为 开发能够改善临床结果的个性化治疗至关重要。精神和精神方面的改变 心理状态，如慢性压力、抑郁和焦虑症，可能会加速肿瘤的生长 并促进对化疗治疗的抗药性。这些生物行为紊乱的后果 明显见于卵巢癌患者，因为这些女性报告了显著的心理水平 苦恼。这些疾病与交感神经系统的持续激活有关。 导致肿瘤微环境中儿茶酚胺水平升高和炎症。促炎因子 核因子-kB信号通路等通路与卵巢癌的生长和进展有关。 作为一个长期目标，这项建议旨在研究慢性压力导致 卵巢癌的进展。为了解决这一目标，我们将研究IKBKE和NF-kB信号转导的作用 肾上腺素能诱导卵巢癌进展的途径。我们的中心假设是激活 IKBKE通过肾上腺素能信号促进卵巢癌进展。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活性是否导致核因子-kB效应器和 随后的体外转录活性。我们将评估核因子-kB的磷酸化模式和转录 确定儿茶酚胺是否诱导IKBKE磷酸化和导致核因子-kB转录的靶基因 活动。具体目标2将侧重于确定儿茶酚胺诱导的IKBKE激活是否介导了促肿瘤 卵巢癌的细胞变化。通过功能分析，我们将研究IKBKE激活对 卵巢癌细胞的侵袭潜能和炎症状态。此外，我们将评估IKBKE的激活和 其与卵巢癌患者病情进展的相关性。最后，具体目标3将研究需求 在两种活体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。通过 产生的数据提供了关于慢性压力如何导致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，以提高生活质量 以及美国和波多黎各的存活率。

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.