The paradoxical roles of beta hydroxy butyrate in the liver pro-metastatic niche

β-羟基丁酸在肝脏促转移生态位中的矛盾作用

• 批准号: 10745869
• 负责人: Neil A. Bhowmick
• 金额: $ 14.09万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-21 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10745869
• 关键词: Affect; Breast Cancer Cell; Butyrates; Cells; Colon Carcinoma; Colorectal; Data; Diagnostic Neoplasm Staging; Diet; Endocrine; Energy-Generating Resources; Fasting; Fatty Acids; Fatty acid glycerol esters; Healthcare; Histone Deacetylase Inhibitor; Immune checkpoint inhibitor; Ketoses; Ketosis; Liver; Malignant Neoplasms; Malignant neoplasm of prostate; Metabolic; Metabolism; Metastatic Neoplasm to the Liver; Metastatic to; Mission; Modeling; Neoplasm Metastasis; Neurodegenerative Disorders; Nicotinic Acids; Nutritional; Organ; Pancreatic Ductal Adenocarcinoma; Patient Care; Patients; Primary Neoplasm; Prostate; Reporting; Research; Role; Signal Transduction; Signaling Molecule; Site; Stress; Tumor Suppressor Proteins; United States National Institutes of Health; Warburg Effect; cancer stem cell; cancer therapy; cancer type; carcinogenesis; improved; innovation; ketogenesis; ketogenic diet; ketogentic; metastatic colorectal; receptor; tumor progression

Project Summary/Abstract Liver metastasis is a steep obstacle for curative cancer treatment. Several cancers including prostate (PCa), colorectal (CRC) and pancreatic ductal adenocarcinoma (PDAC) commonly metastasize to this site. Data shows that liver metastasis is promoted by endocrine signaling from the primary tumor which can transform the liver microenvironment. Nonetheless, this pre-metastatic to post-metastatic niche transformation can also be influenced by therapy and diet. The ketogenic diet (KD) is a high-fat carb-restrictive diet that mimics fasting by making fatty acids the main source of energy and promoting beta hydroxy butyrate (βHB) synthesis (ketosis). KD has been successfully used to aid patients with neurodegenerative diseases. Additionally, it has been proposed to ameliorate different types of cancer by inducing a reverse-Warburg effect and sensitizing cells to checkpoint inhibitors. However, reports show that βHB enables adaptability to nutritional stress in cancer stem cells and is associated with tumor progression and staging of prostate cancer. Nevertheless, βHB is also a reported tumor suppressor being a known HDAC inhibitor and a signaling molecule through the niacin receptor, GPR109a, in colon and breast cancer cells. Understanding that the liver is the main βHB synthesis organ, in this study we aim to elucidate the effects of a ketogenic metabolism affecting the liver premetastatic niche and its paradoxical roles with PCa and CRC in their distinct metabolic reprogramming.

项目摘要/摘要 肝转移是根治性癌症治疗的一大障碍。几种癌症，包括前列腺癌(PCa)， 结直肠癌(CRC)和胰腺导管腺癌(PDAC)通常转移到这个部位。数据显示 肝转移是由原发肿瘤的内分泌信号促进的，这种信号可以改变肝脏 微环境。尽管如此，这种转移前到转移后的生态位转变也可以是 受治疗和饮食的影响。生酮饮食(KD)是一种模拟禁食的高脂肪碳水化合物饮食 使脂肪酸成为主要的能量来源，并促进β-羟基丁酸酯(β-Hb)的合成(酮病)。 KD已成功地用于帮助神经退行性疾病患者。此外，它一直是 提出通过诱导反向Warburg效应和使细胞敏化来改善不同类型的癌症 检查点抑制药。然而，有报道表明，βHB能够使癌症干细胞适应营养压力 并且与前列腺癌的肿瘤进展和分期有关。尽管如此，βHB也是一家 已报道的肿瘤抑制物是一种已知的HDAC抑制剂和通过烟酸受体的信号分子， Gpr109a，在结肠癌和乳腺癌细胞中。理解肝脏是主要的βHb合成器官，在这方面 我们的研究目的是阐明生酮代谢对肝脏转移前生态位的影响及其 PCA和CRC在其不同的代谢重新编程中的矛盾角色。