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

基本信息

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
项目类别：
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

项目摘要

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）：肺癌是第二常见的癌症，是癌症相关死亡的主要原因，并且不成比例地影响服务不足的少数群体。五年生存率仅为 15%，这凸显了需要开发新的生物标志物和治疗靶点，分别用于早期检测和选择性治疗。大多数肺癌与炎症增加有关，环氧合酶 (COX) 表达和 COX 衍生前列腺素（包括前列腺素 E2 (PGE2)）合成升高证明了这一点。这些生物活性脂质已成为多种组织（包括肺）致癌的中心调节因子。特别是，PGE2 合成的调节与肺癌发生密切相关：PGE2 在肺部肿瘤中升高。 PGE2 水平的增加通过增加细胞生长和侵袭来促进肺癌的发生，而 PGE2 的消耗则抑制肺癌的发生。减少前列腺素合成的药物的鉴定是一个活跃的研究领域。诱导型 COX-2 酶的药理学抑制已被探索，但其使用与潜在的致命副作用有关。我们的实验室正在研究一种新型细胞色素 P450（CYP2S1）在肺癌发生中的调节作用。我们假设 CYP2S1 表达和酶功能的变化通过遗传变异调节人肺癌细胞中 PGE2 的合成，从而调节 PGE2 相关细胞的生长和侵袭。这一假设得到以下支持：i) CYP2S1 在接近生理水平介导 PGE2 前体前列腺素 G2 (PGG2) 的代谢 - 最终减少 PGE2 合成，以及 ii) 我们的初步数据与这一作用一致，显示：CYP2S1 的表达与细胞内 PGE2 水平以及 CYP2S1 耗尽以及随后 PGE2 水平增加促进人支气管上皮细胞中的细胞迁移（BEAS-2B）。此外，我们还对一种与癌症相关的遗传多态性进行了建模，该多态性独特地分布在非裔美国人群体中，靠近假定的底物进入通道的开放——可能表明 CYP2S1 多态性与该群体中的肺癌发生有关。我们将结合细胞和生化方法来解决我们的假设，并确定 CYP2S1 表达 (Aim1) 和功能 (Aim2) 对肺癌发生的影响。该提案意义重大，因为它：i) 确立了 CYP2S1 在调节肺癌中前列腺素合成和 PGE2 相关表型中的重要生物学作用，ii) 表明 CYP2S1 表达升高在上皮源性癌症中具有保护作用，以及 iii) 正在开发用于未来 CYP2S1 选择性药物测试的敏感生化和基于细胞的方法。这些研究有可能改变当前的研究以及未来潜在的临床范式。