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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：
9365189
负责人：
Maria Teresa Diaz Meco Conde
金额：
$ 57.9万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
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/9365189
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 Epithelium 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 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.

总结