Peroxisome Proliferator Activated Receptors in Lung Cancer

肺癌中的过氧化物酶体增殖物激活受体

• 批准号: 7409657
• 负责人: RAPHAEL A. NEMENOFF
• 金额: $ 28.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-05 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409657
• 关键词: 2,4-thiazolidinedione; 3-Dimensional; Accounting; Adenomatous Polyposis Coli; Affect; Agar; Anchorage-Independent Growth; Anti-Inflammatory Agents; Anti-inflammatory; Antidiabetic Drugs; Antineoplastic Agents; Apoptosis; Binding; Cancer cell line; Cells; Cellular Morphology; Colon; Colon Carcinoma; Colonic Neoplasms; Colorado; Conflict (Psychology); DNA Sequence; Data; Development; Eicosanoids; Enzymes; Epoprostenol; Extracellular Matrix; Gene Expression; Genes; Genus Cola; Goals; Growth; Human; Iloprost; In Vitro; Integrins; Laboratories; Ligands; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Modeling; Molecular; Molecular Profiling; Mus; Non-Small-Cell Lung Carcinoma; Nuclear Hormone Receptors; Nude Mice; Outcome; PPAR alpha; PPAR delta; PPAR gamma; Pathologic; Pathway interactions; Pattern; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Prostaglandins D; Prostaglandins I; Protein C; Protein Isoforms; Protein Overexpression; Protocols documentation; Rattus; Receptor Activation; Reproduction spores; Research Personnel; Role; Sampling; Signal Pathway; Testing; Therapeutic Intervention; Thiazolidinediones; Tissue Microarray; Transgenic Mice; Tretinoin; Tumor Suppressor Proteins; Tumorigenicity; Universities; Xenograft Model; activating transcription factor; adipocyte differentiation; analog; cancer cell; cancer type; carcinogenesis; cell growth; cell motility; cell type; ciglitazone; clinical Diagnosis; in vivo; lung small cell carcinoma; lung tumorigenesis; member; migration; neoplastic cell; programs; promoter; receptor; receptor expression; response; surfactant; tissue culture; troglitazone; tumorigenesis; tumorigenic; two-dimensional

DESCRIPTION (provided by applicant): Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily which act as ligand-activated transcription factors. Three isoforms have been identified, PPAR alpha, gamma, and delta, all of which bind to specific DNA sequences as heterodimers with the retinoic acid X-receptors. PPARgamma has been shown to be activated by the synthetic antidiabetic thiazolidinediones (TZD) such as ciglitazone and troglitazone as well as by prostaglandin D and J derivatives which may function as endogenous activators. While an important role for PPARgamma has been defined in adipocyte differentiation, this molecule is expressed in a variety of cell types including non-small cell lung cancer cells (NSCLC). Data from our laboratory and other investigators have shown that activators of PPARgamma inhibit transformed growth of NSCLC. However, these agents engage additional pathways, and conflicting data has been obtained in other types of cancer, indicating both a pro- and anti-tumorigenic role for PPARs. PPARdelta has been shown to be activated by prostacyclin and its stable analog iloprost. The role of PPARdelta in the development cancer is also not clear, with studies demonstrating both a tumorigenic and anti-tumorigenic role. Preliminary studies from our laboratory have shown that overexpression of PPARgamma in multiple NSCLC lines selectively inhibited anchorage-independent growth in soft agar in vitro, and the development of lung tumors in xenograft models. Analysis of gene expression using microarrays suggests that these inhibitory effects may be mediated through altered expression of integrins and enzymes that modulate extracellular matrix, implicating alterations in cell migration and invasion. Overexpression of PPARdelta in NSCLC inhibits PPARgamma activity and leads to increased soft agar colony formation. For both isoforms of PPAR the molecular mechanisms whereby PPARs regulate lung tumorigenesis are poorly understood. The goal of this proposal is to employ molecular and pharmacological approaches to test the hypothesis that activation of specific PPAR isoforms has opposing effects on the development of lung cancer, and to identify potential mechanisms which may account for these effects. Four specific aims are proposed. Specific aim 1 will examine the effects of overexpressing PPARgamma and delta on the transformed growth of NSCLC lines, and compare the response with effects of putative specific pharmacological agents. Specific Aim 2 will define the molecular changes induced by overexpression of PPARs on cell morphology, migration and differentiation, using 2-dimensional and three dimensional tissue culture. Specific Aim 3 will develop transgenic mice specifically overexpressing PPARs, and assess their role in carcinogenesis models. Specific Aim 4 will examine PPAR expression using a tissue microarray derived from human lung cancer samples. These studies will help to define the role of PPARs in lung tumorigenesis, and help to define new targets for therapeutic intervention.

描述（由申请人提供）：过氧化物酶体增殖物激活受体（PPAR）是核激素受体超家族的成员，其充当配体激活转录因子。已鉴定出三种同工型：PPAR α、γ 和 δ，所有这些同工型均与视黄酸 X 受体形成异二聚体，与特定 DNA 序列结合。 PPARγ 已被证明可被合成抗糖尿病药物噻唑烷二酮 (TZD)（例如环格列酮和曲格列酮）以及可作为内源性激活剂的前列腺素 D 和 J 衍生物激活。虽然 PPARgamma 在脂肪细胞分化中发挥着重要作用，但该分子在多种细胞类型中表达，包括非小细胞肺癌细胞 (NSCLC)。我们实验室和其他研究人员的数据表明，PPARγ 激活剂可抑制 NSCLC 的转化生长。然而，这些药物涉及其他途径，并且在其他类型的癌症中获得了相互矛盾的数据，表明 PPAR 具有促肿瘤和抗肿瘤作用。 PPARδ 已被证明可被前列环素及其稳定类似物伊洛前列素激活。 PPARδ 在癌症发展中的作用也尚不清楚，研究表明其具有致瘤和抗肿瘤作用。我们实验室的初步研究表明，多个 NSCLC 系中 PPARgamma 的过表达选择性抑制体外软琼脂中的贴壁非依赖性生长，以及异种移植模型中肺肿瘤的发展。使用微阵列对基因表达的分析表明，这些抑制作用可能是通过改变整合素和调节细胞外基质的酶的表达来介导的，这意味着细胞迁移和侵袭的改变。 NSCLC 中 PPARδ 的过度表达会抑制 PPARgamma 活性并导致软琼脂集落形成增加。对于 PPAR 的两种亚型，PPAR 调节肺部肿瘤发生的分子机制尚不清楚。该提案的目标是采用分子和药理学方法来检验特定 PPAR 同工型的激活对肺癌的发展具有相反作用的假设，并确定可能解释这些作用的潜在机制。提出了四个具体目标。具体目标 1 将检查过表达 PPARgamma 和 delta 对 NSCLC 系转化生长的影响，并将反应与推定的特定药物的效果进行比较。具体目标 2 将使用二维和三维组织培养来定义 PPAR 过度表达对细胞形态、迁移和分化引起的分子变化。 Specific Aim 3 将开发特异性过表达 PPAR 的转基因小鼠，并评估它们在致癌模型中的作用。具体目标 4 将使用源自人类肺癌样本的组织微阵列检查 PPAR 表达。这些研究将有助于明确 PPAR 在肺肿瘤发生中的作用，并有助于确定治疗干预的新靶点。