ROLE OF CYP24 IN NON-SMALL CELL LUNG CANCER
CYP24 在非小细胞肺癌中的作用
基本信息
- 批准号:7726079
- 负责人:
- 金额:$ 28.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-05-21 至 2011-04-30
- 项目状态:已结题
- 来源:
- 关键词:25-hydroxycholecalciferol-24-hydroxylaseBindingBiologicalBiological AssayCCAAT-Enhancer-Binding ProteinsCalcitriolCancer cell lineCatabolismCholecalciferolDNA BindingDataDiagnosisDiseaseDrug KineticsEnzymesEquilibriumGenetic TranscriptionGrowthHormonesHumanIn VitroIndividualLeadLinkLuciferasesLung NeoplasmsMalignant neoplasm of lungMediatingNon-Small-Cell Lung CarcinomaOncogene ActivationOncogenesOncogenicPathogenesisPathway interactionsPhenotypeProductionProteinsRegulationRegulatory PathwayReporterResearch DesignRoleSignal PathwaySignal TransductionSmall Interfering RNAStructure of parenchyma of lungTestingTherapeuticTissuesUnited StatesVitamin DXenograft Modelactivating transcription factorantitumor agentautocrinecancer cellchromatin immunoprecipitationclinically relevantin vivoinhibitor/antagonistinnovationinsightlung cancer preventionlung tumorigenesismRNA Expressionneoplastic cellnoveloverexpressionpromoterpublic health relevanceresponsetranscription factortumortumor xenografttumorigenesis
项目摘要
DESCRIPTION (provided by applicant): Our studies have led to the identification of a novel growth regulatory pathway in non-small cell lung cancer (NSCLC) that involves CYP24, the enzyme that degrades the endogenous anti-proliferative agent, 1,25- dihydroxyvitamin D3 (1,25(OH)2D3). The level and biological activity of 1,25(OH)2D3 in tissues is normally controlled by maintaining a precise balance between the rates of its synthesis by CYP27B1 and degradation by CYP24. We discovered that this balance is dysregulated in NSCLC. Specifically, we determined that CYP24 is overexpressed in human NSCLC cells and a majority of human lung tumors. We hypothesize that CYP24 overexpression facilitates lung cancer growth by allowing neoplastic cells to escape the anti- proliferative effects of locally-produced 1,25(OH)2D3. Accordingly, we found that CYP24 inhibition uncovers 1,25(OH)2D3 production by CYP27B1+CYP24+ NSCLC cells and allows for accumulation of hormone in amounts sufficient for growth suppression. Our data further indicate that Ets-1 and C/EBP proteins increase CYP24 transcription in NSCLC cells. Activation of these transcription factors has previously been linked to oncogenic signaling in lung cancer. Our objective is to establish the effect of aberrant CYP24 expression on lung cancer growth and the mechanism for CYP24 overexpression in lung cancer. In Aim 1 we will test the prediction that CYP24 overexpression facilitates NSCLC growth by decreasing the stability and anti- tumor activity of 1,25(OH)2D3. We will quantify the effect of modulating CYP24 expression on 1,25(OH)2D3 catabolism and anti-tumor activity in NSCLC cell lines and tumor xenograft models. We will also use an innovative ex vivo assay to determine the association between CYP24 expression and 1,25(OH)2D3 catabolism in human lung tumors. In Aim 2 we will test the prediction that CYP24 overexpression antagonizes autocrine growth regulation by vitamin D3 in NSCLC. We will utilize a novel CYP24 inhibitor to demonstrate the effect of CYP24 on 1,25(OH)2D3 synthesis by CYP27B1+CYP24+ NSCLC cells and demonstrate the ability of locally- produced hormone to elicit biological responses. We will also test whether CYP24 overexpression and CYP27B1 loss are independently correlated with the lung cancer phenotype. In Aim 3 we will test the prediction that oncogene-activated Ets-1 and C/EBP transcription factors regulate CYP24 expression in NSCLC. The effect of Ets-1 and C/EBP modulation on CYP24 transcription and activity will be established. Recruitment of Ets and C/EBP proteins to the endogenous CYP24 promoter (as a function of ras activation) will be evaluated by chromatin immunoprecipitation. The proposed studies will identify a novel mechanism for the pathogenesis of NSCLC in which oncogene-activated transcription factors facilitate tumorigenesis by increasing the expression of a protein (CYP24) that catabolizes an endogenous growth suppressor (1,25(OH)2D3). The therapeutic implication of this paradigm, once confirmed, is that agents that inhibit CYP24 can be used to restore vitamin D3-mediated growth control in NSCLC. PUBLIC HEALTH RELEVANCE: We recently discovered that lung cancer cells make a protein called CYP24 that destroys the natural anti-tumor agent, vitamin D. Our studies are designed to determine the precise role of CYP24 in promoting lung cancer growth. Ultimately, this will help us to develop optimized strategies to block CYP24 and thereby increase the activity of vitamin D in lung cancer prevention and treatment.
描述(申请人提供):我们的研究已经在非小细胞肺癌(NSCLC)中发现了一种新的生长调节途径,它涉及降解内源性抗增殖剂1,25-二羟基维生素D3(1,25(OH)2D3)的酶--细胞色素P24。1,25(OH)2D3在组织中的水平和生物活性通常是通过维持其由CYP27B1合成和由CYP24降解之间的精确平衡来控制的。我们发现,在非小细胞肺癌中,这种平衡是失调的。具体地说,我们确定了CYP24在人类非小细胞肺癌细胞和大多数人类肺部肿瘤中过表达。我们假设,通过让肿瘤细胞逃避局部产生的1,25(OH)2D3的抗增殖作用,细胞色素P24的过表达促进了肺癌的生长。因此,我们发现,抑制CYP24发现了CYP27B1+CYP24+NSCLC细胞产生1,25(OH)2D3,并允许激素积累到足以抑制生长的数量。我们的数据进一步表明,Ets-1和C/EBP蛋白促进了非小细胞肺癌细胞中CYP24的转录。这些转录因子的激活以前被认为与肺癌的致癌信号有关。本研究的目的是探讨细胞色素P24基因异常表达对肺癌生长的影响,以及细胞色素P24在肺癌中过表达的机制。在目标1中,我们将通过降低1,25(OH)2D3的稳定性和抗肿瘤活性来检验CYP24过表达促进NSCLC生长的预测。我们将在非小细胞肺癌细胞系和肿瘤异种移植模型中量化调控细胞色素P24表达对1,25(OH)2D3分解代谢和抗肿瘤活性的影响。我们还将使用一种创新的体外试验来确定CYP24在人类肺癌中的表达和1,25(OH)2D3分解代谢之间的关系。在目标2中,我们将验证在非小细胞肺癌中,细胞色素P24的过度表达对抗维生素D3对自分泌生长调节的预测。我们将利用一种新的细胞色素P24抑制剂来证明细胞色素P24对细胞合成1,25(OH)2D3的影响,并证明局部产生的激素能够引起生物反应。我们还将测试细胞色素P24的过度表达和细胞色素P27B1的缺失是否与肺癌表型独立相关。在目标3中,我们将验证癌基因激活的Ets-1和C/EBP转录因子调控非小细胞肺癌细胞色素P24表达的预测。Ets-1和C/EBP调控对细胞色素P24转录和活性的影响将被证实。染色质免疫沉淀法将评估Ets和C/EBP蛋白在内源性CYP24启动子上的募集(作为ras激活的功能)。拟议的研究将确定NSCLC发病机制的新机制,在该机制中,癌基因激活的转录因子通过增加内源性生长抑制因子(1,25(OH)2D3)分解代谢的蛋白质(CYP24)的表达来促进肿瘤的发生。这一范例的治疗意义是,一旦得到证实,抑制CYP24的药物可以用于恢复维生素D3介导的非小细胞肺癌的生长控制。与公共健康相关:我们最近发现,肺癌细胞会产生一种名为CYP24的蛋白质,这种蛋白质会破坏天然的抗肿瘤药物维生素D。我们的研究旨在确定CYP24在促进肺癌生长方面的确切作用。最终,这将有助于我们开发优化的策略来阻断CYP24,从而提高维生素D在肺癌预防和治疗中的活性。
项目成果
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PAMELA A HERSHBERGER其他文献
PAMELA A HERSHBERGER的其他文献
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{{ truncateString('PAMELA A HERSHBERGER', 18)}}的其他基金
Summer Research Experiences in Cancer Science and Oncology
癌症科学和肿瘤学夏季研究经验
- 批准号:
10672229 - 财政年份:2014
- 资助金额:
$ 28.29万 - 项目类别:
Summer Research Experiences in Cancer Science and Oncology
癌症科学和肿瘤学夏季研究经验
- 批准号:
10480076 - 财政年份:2014
- 资助金额:
$ 28.29万 - 项目类别:
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癌症科学和肿瘤学夏季研究经验
- 批准号:
10246505 - 财政年份:2014
- 资助金额:
$ 28.29万 - 项目类别:
ROLE OF CYP24 IN NON-SMALL CELL LUNG CANCER
CYP24 在非小细胞肺癌中的作用
- 批准号:
8193214 - 财政年份:2009
- 资助金额:
$ 28.29万 - 项目类别:
ROLE OF CYP24 IN NON-SMALL CELL LUNG CANCER
CYP24 在非小细胞肺癌中的作用
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8257964 - 财政年份:2009
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$ 28.29万 - 项目类别:
ROLE OF CYP24 IN NON-SMALL CELL LUNG CANCER
CYP24 在非小细胞肺癌中的作用
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8473825 - 财政年份:2009
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