Role of p62 in metabolic reprograming of the tumor stroma in prostate cancer

p62 在前列腺癌肿瘤基质代谢重编程中的作用

基本信息

批准号：
10220897
负责人：
Maria Teresa Diaz Meco Conde
金额：
$ 50.01万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220897
关键词：
Address Amino Acids Asparagine Aspartate-Ammonia Ligase Biological Cancer Biology Carcinoma Clinical Communication Complex Data Down-Regulation Environment Enzymes Epithelial Epithelial Cells Event Fibroblasts Gene Expression Genetic Enhancer Element Genetic Transcription Glucose Glutamine Glycine Goals Growth Human Malignant neoplasm of prostate Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Molecular Nutrient Nutritional Oxaloacetates Pathway interactions Phenotype Play Process Proliferating Prostate Pyruvate Carboxylase Pyruvate Metabolism Pathway Regulation Repression Resistance Role Serine Signal Pathway Signal Transduction Site Stress Stromal Cells Testing Transcription Factor AP-1 Up-Regulation base cancer cell deprivation folic acid metabolism glucose metabolism in vivo innovation new therapeutic target novel therapeutic intervention prevent programs promoter prostate cancer cell prostate cancer progression response transcription factor tumor tumor metabolism tumor microenvironment tumor progression tumorigenesis

项目摘要

SUMMARY The process by which not only cancer cells but also other components of the tumor microenvironment respond to nutritionally challenging conditions is not well known. The proposed study will provide a detailed understanding of the mechanisms whereby the PCa epithelium educates the stroma by downregulating p62, and how p62-deficient stroma reprograms its metabolism to generate a microenvironment more resistant to nutrient stress. This application is based on two sets of preliminary data: 1) p62-deficient stromal cells reprogram their metabolism to mediate stromal resistance to glutamine (Gln) deprivation, and promote the growth of PCa epithelial cells even under Gln-limiting conditions; 2) stromal p62 is downregulated by lactate secreted by the PCa epithelium by JunB-mediated repression of the p62-promoter. Based on these data, we hypothesize that p62 downregulation in the stroma by PCa cells constitutes a tumor strategy for the PCa epithelium to obtain the metabolic support necessary to proliferate under the Gln-deprived tumor microenvironment. We will address this fundamental problem in cancer biology in the following Aims: (1) Define how p62 deficiency reprograms stromal metabolism in Gln-deprived conditions. We hypothesize that ATF4 upregulation is central to the mechanisms whereby the loss of p62 in stromal cells reprograms glucose metabolism to compensate for the lack of Gln. To test this hypothesis, we will: (1A) Mechanisms of ATF4 regulation by the p62-PKCλ/ι complex; (1B) Define how p62 deficiency reprograms serine/glycine metabolism in response to Gln deprivation through PKCλ/ι-ATF4; (1C) Define how p62 deficiency promotes Asn synthesis in response to Gln deprivation through PKCλ/ι-ATF4; (1D) Define how the p62-PKCλ/ι-ATF4 signaling cascade regulates pyruvate metabolism; (1E) Determine the functional relevance of p62-dependent stromal metabolic reprograming in PCa in vivo. (2) Define how p62 is downregulated by PCa in the tumor stroma: To unravel the mechanisms that regulate p62 repression in this context, we will: (2A) Identify the lactate- responsive AP-1 site in the p62 promoter; (2B) Characterize the JunB-containing AP-1 complex regulated by lactate; (2C) Define the role of NRF2 in JunB-mediated p62 repression; (2D) Define the biological relevance of the identified transcription factors and signaling pathways that induce p62-downregulation. This innovative proposal will fill a key gap in the cancer metabolism field by defining the relationship between metabolic rewiring and signaling in the tumor stroma and its impact on PCa progression. The impact of these findings will instruct new therapeutic strategies aimed at manipulating the metabolism of the stroma.

概括不仅是癌细胞，而且肿瘤微环境的其他成分也做出反应的过程所提出的研究将提供详细的营养挑战条件。了解 PCa 上皮通过下调 p62 来教育基质的机制，以及 p62 缺陷基质如何重新编程其新陈代谢以产生更具抵抗力的微环境该应用基于两组初步数据：1) p62 缺乏的基质细胞。重新编程它们的新陈代谢以介导基质对谷氨酰胺 (Gln) 缺乏的抵抗力，并促进即使在 Gln 限制条件下，PCa 上皮细胞也能生长；2) 基质 p62 会被乳酸下调；由 JunB 介导的 p62 启动子抑制由 PCa 上皮分泌。 PCa 细胞基质中 p62 的下调构成了 PCa 的肿瘤策略上皮获得在谷氨酰胺缺乏的肿瘤下增殖所需的代谢支持我们将通过以下目标解决癌症生物学中的这一基本问题：（1）定义 p62 缺乏症如何在 Gln 缺乏的条件下重新编程基质代谢。 ATF4 上调是基质细胞中 p62 缺失重新编程葡萄糖机制的核心为了验证这一假设，我们将： (1A) ATF4 的机制。 p62-PKCλ/ι 复合物的调节；(1B) 定义 p62 缺陷如何重新编程丝氨酸/甘氨酸代谢通过 PKCλ/ι-ATF4 响应 Gln 剥夺；(1C) 定义 p62 缺乏如何促进 Asn 合成通过 PKCλ/ι-ATF4 响应 Gln 剥夺 (1D) 定义 p62-PKCλ/ι-ATF4 信号传导如何进行 (1E) 确定 p62 依赖性基质的功能相关性 PCa 体内代谢重编程 (2) 定义肿瘤基质中 p62 如何被 PCa 下调：为了揭示在这种情况下调节 p62 抑制的机制，我们将： (2A) 识别乳酸- p62 启动子中的响应性 AP-1 位点；(2B) 表征包含 JunB 的 AP-1 复合物受调节 (2C) 定义 NRF2 在 JunB 介导的 p62 抑制中的作用；(2D) 定义其生物学相关性已鉴定出诱导 p62 下调的转录因子和信号通路。该提案将通过定义代谢之间的关系来填补癌症代谢领域的关键空白肿瘤基质中的重新布线和信号转导及其对 PCa 进展的影响。指导旨在操纵基质代谢的新治疗策略。