Bioactive lipids in lung carcinogenesis: A modulatory role for CYP2S1

肺癌发生中的生物活性脂质：CYP2S1 的调节作用

• 批准号: 8414610
• 负责人: AARON M ROWLAND
• 金额: $ 14.6万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8414610
• 关键词: A549; Address; Adverse effects; Affect; African American; Apoptosis; Area; Biochemical; Biological; Biological Markers; CYP2S1 gene; Cancer Center; Cancer Etiology; Cancer cell line; Cancerous; Cells; Clinical; Cytochrome P450; Data; Development Plans; Dinoprostone; Doctor of Medicine; Drug Targeting; Early Diagnosis; Ensure; Enzymes; Epithelial; Epithelial Cells; Foundations; Funding; Future; Genetic Polymorphism; Hepatic Tissue; Human; Inflammation; Laboratories; Link; Lipids; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metabolism; Modeling; Oregon; Pathway interactions; Pattern; Pharmacologic Substance; Phenotype; Physiological; Population; Predisposition; Process; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protocols documentation; Research; Role; Structure of parenchyma of lung; Survival Rate; Testing; Therapeutic; Tissue Microarray; Tissues; Underrepresented Minority; Universities; Variant; base; cancer cell; carcinogenesis; career development; cell growth; cell motility; cyclooxygenase 2; genetic variant; lung carcinogenesis; migration; mortality; neoplastic cell; new therapeutic target; novel; professor; prostaglandin G2; public health relevance; selective expression; therapeutic target

DESCRIPTION (provided by applicant): Lung cancer is the second most prevalent form of cancer, the leading cause of cancer-related mortality, and disproportionately affects underserved minority populations. The five-year survival rate is a dismal 15 percent - emphasizing the need to develop novel biomarkers and therapeutic targets for early detection and selective treatment, respectively. The majority of lung cancers are associated with increased inflammation, as evidenced by elevated cyclooxygenase (COX) expression and synthesis of COX-derived prostaglandins, including prostaglandin E2 (PGE2). These bioactive lipids have emerged as central regulators of carcinogenesis in a variety of tissues, including the lung. In particular, modulation of PGE2 synthesis is strongly correlated with lung carcinogenesis: PGE2 is elevated in lung tumors. Increased levels of PGE2 promote lung carcinogenesis by increasing cell growth and invasion while PGE2 depletion inhibits lung carcinogenesis. Identification of pharmaceuticals that reduce prostaglandin synthesis is an active area of research. Pharmacological inhibition of the inducible COX-2 enzyme has been explored, however its use is associated with potentially lethal side effects. Our laboratory is examining the modulatory role of a novel cytochrome P450, CYP2S1, in lung carcinogenesis. We hypothesize that changes in CYP2S1 expression and enzymatic function, through genetic variants, regulates PGE2 synthesis in human lung cancer cells to modulate PGE2-associated cell growth and invasion. This hypothesis is supported by: i) CYP2S1 mediated metabolism of the PGE2 precursor prostaglandin G2 (PGG2) at near physiological levels - ultimately reducing PGE2 synthesis, and ii) our preliminary data, consistent with this role, showing: CYP2S1's expression is inversely related to intracellular PGE2 levels and that CYP2S1 depletion, and subsequent increased PGE2 levels, promotes cell migration in human bronchial epithelial cells (BEAS-2B). Furthermore, we have modeled a genetic polymorphism, associated with cancer and uniquely distributed among African American populations, near the opening of a putative substrate access channel - potentially implicating CYP2S1 polymorphisms to lung carcinogenesis in this population. We will address our hypothesis, and determine the impact of CYP2S1 expression (Aim1) and function (Aim2), on lung carcinogenesis using a combination of cell-based and biochemical approaches. This proposal is significant because it: i) establishes an important biological role for CYP2S1 in modulating prostaglandin synthesis and PGE2-associated phenotypes in lung cancer, ii) suggests a protective role for elevated expression of CYP2S1 in epithelial-derived cancer, and iii) develops sensitive biochemical and cell-based approaches for the future testing of CYP2S1-selective pharmaceuticals. These studies have the potential to alter current research, and potential future clinical, paradigms.

描述（由申请人提供）：肺癌是癌症的第二大流行形式，是癌症相关死亡率的主要原因，并且不成比例地影响服务不足的少数群体。五年生存率是15％的惨淡 - 强调需要开发新型的生物标志物和治疗靶标，以分别进行早期检测和选择性治疗。大多数肺癌与炎症的增加有关，这是通过环氧酶（COX）表达升高和COX衍生前列腺素的合成所证明的，包括前列腺素E2（PGE2）。这些生物活性脂质已成为包括肺在内的多种组织中癌变的中心调节剂。特别是，PGE2合成的调节与肺癌发生密切相关：肺部肿瘤中PGE2升高。 PGE2水平的升高通过增加细胞生长和浸润来促进肺癌发生，而PGE2消耗抑制了肺癌的发生。鉴定减少前列腺素合成的药物是一个活跃的研究领域。已经探索了对诱导型COX-2酶的药理抑制作用，但是其使用与潜在的致命副作用有关。我们的实验室正在研究新型细胞色素P450，CYP2S1在肺癌发生中的调节作用。我们假设CYP2S1表达和酶促功能的变化通过遗传变异来调节人肺癌细胞中的PGE2合成，以调节与PGE2相关的细胞生长和侵袭。该假设得到以下支持：i）CYP2S1在接近生理水平上介导的PGE2前体前列腺素G2（PGG2）的代谢 - 最终降低了PGE2合成，ii）我们的初步数据，与此作用相一致，显示了：CYP2S1的表达与Intervelly Intrevers and Aversect and cyt 2级别和Intrevellible pge2级别和cipt 2级相关。 PGE2水平，促进人支气管上皮细胞（BEAS-2B）的细胞迁移。此外，我们已经建模了一种遗传多态性，与癌症相关，并在非裔美国人种群中分布在假定的底物通道渠道附近，这可能暗示CYP2S1多态性与该人群中的肺癌发生。我们将解决CYP2S1表达（AIM1）和功能（AIM2）对肺癌发生的影响，并确定CYP2S1表达（AIM1）和功能的影响。 This proposal is significant because it: i) establishes an important biological role for CYP2S1 in modulating prostaglandin synthesis and PGE2-associated phenotypes in lung cancer, ii) suggests a protective role for elevated expression of CYP2S1 in epithelial-derived cancer, and iii) develops sensitive biochemical and cell-based approaches for the future testing of CYP2S1-selective pharmaceuticals.这些研究有可能改变当前的研究和潜在的未来临床范例。