The Role of PHLPP in Colon Cancer

PHLPP 在结肠癌中的作用

• 批准号: 9178592
• 负责人: Tianyan Gao
• 金额: $ 35.74万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178592
• 关键词: Adenocarcinoma; Adipocytes; Affect; Automobile Driving; Cancer Cell Growth; Cancer Center; Cancer Etiology; Cell Proliferation; Cell Survival; Cells; Cessation of life; Citric Acid Cycle; Collection; Colon Carcinoma; Colorectal Cancer; Development; Down-Regulation; Ensure; Event; FRAP1 gene; Genetic; Human; Hypoxia; In Vitro; Intestines; Knockout Mice; Knowledge; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Molecular; NOD/SCID mouse; Oncogenes; PH Domain; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Production; Protein Family; Protein phosphatase; Proteins; Ras/Raf; Regulation; Research; Resistance; Role; Signal Transduction; Testing; Tissues; Translations; Treatment Efficacy; Tumor Suppressor Proteins; United States; Xenograft Model; cancer cell; cancer initiation; cancer therapy; chemotherapy; colon cancer patients; colon tumorigenesis; design; experimental study; glucose uptake; improved; in vivo; insight; leucine-rich repeat protein; lipid biosynthesis; lipid metabolism; mTOR Inhibitor; macromolecule; metabolomics; mouse model; novel; outcome forecast; public health relevance; stable isotope; success; therapy resistant; treatment strategy; tumor metabolism; tumor progression; tumorigenesis; Adenocarcinoma; Adipocytes; Affect; Automobile Driving; Cancer Cell Growth; Cancer Center; Cancer Etiology; Cell Proliferation; Cell Survival; Cells; Cessation of life; Citric Acid Cycle; Collection; Colon Carcinoma; Colorectal Cancer; Development; Down-Regulation; Ensure; Event; FRAP1 gene; Genetic; Human; Hypoxia; In Vitro; Intestines; Knockout Mice; Knowledge; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Molecular; NOD/SCID mouse; Oncogenes; PH Domain; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Production; Protein Family; Protein phosphatase; Proteins; Ras/Raf; Regulation; Research; Resistance; Role; Signal Transduction; Testing; Tissues; Translations; Treatment Efficacy; Tumor Suppressor Proteins; United States; Xenograft Model; cancer cell; cancer initiation; cancer therapy; chemotherapy; colon cancer patients; colon tumorigenesis; design; experimental study; glucose uptake; improved; in vivo; insight; leucine-rich repeat protein; lipid biosynthesis; lipid metabolism; mTOR Inhibitor; macromolecule; metabolomics; mouse model; novel; outcome forecast; public health relevance; stable isotope; success; therapy resistant; treatment strategy; tumor metabolism; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Approximately 142,000 new cases and 51,000 deaths are predicted for the year 2013. A better understanding of the molecular events leading to cancer progression and chemoresistance is needed in order to improve the overall survival of CRC patients. Our lab has been intensively focused on elucidating the role of a novel family of protein phosphatases, PHLPP (PH domain Leucine-rich-repeats Protein Phosphatase), in inhibiting CRC initiation and progression. We have made substantial progress in understanding the functional importance of PHLPP as a tumor suppressor as well as the molecular mechanism underlying PHLPP regulation. In this proposed study, we will determine the effect of PHLPP-loss on modulating lipid metabolism in CRC. Although recent advances in cancer metabolism research have begun to elucidate how metabolic changes support cancer cell growth and survival, the regulation and functional importance of altered lipid metabolism in CRC remain elusive. This proposal centers on a novel hypothesis that PHLPP-loss plays a pivotal role in driving CRC progression by promoting lipogenesis. In exciting recent findings, we demonstrate that downregulation of PHLPP expression results in an increase in the expression of activated SREBP1, a key activator of lipid biosynthesis. Consistently, MEF cells isolated from PHLPP knockout mice have enhanced lipogenesis during differentiation into adipocytes. In addition, we have found that silencing PHLPP expression leads to increased glucose uptake, lactate production, Krebs cycle activity, and triacylglycerides accumulation in CRC cells, suggesting a role of PHLPP in regulating cellular metabolism. The central hypothesis driving this proposed study is that PHLPP plays an essential role in inhibiting lipogenesis by negatively regulating the PI3K/Akt/mTOR pathway, and loss of PHLPP expression promotes CRC progression as the result of metabolic reprogramming. The following specific aims are proposed: 1) to delineate the molecular mechanism by which PHLPP regulates lipogenesis in CRC cells. We will perform the Stable Isotope-Resolved Metabolomics (SIRM) analysis to determine how PHLPP-loss affects lipid metabolism in CRC cells; 2) to determine the functional importance of PHLPP-mediated regulation of lipogenesis. We will test if PHLPP-loss renders CRC cells more resistant to metabolic stress and chemotherapy drugs as the result of alterations in lipogenesis; and 3) to define the role of PHLPP in suppressing lipogenesis in vivo. The effect of PHLPP-loss on modulating lipid metabolism will be determined using both genetically modified mouse models and patient-derived xenograft models. Results from our studies will fill an important knowledge gap on how altered lipogenesis affects the prognosis and treatment efficacy in CRC patients. Ultimately, by providing insight into the mechanisms by which PHLPP-mediated lipogenesis, our findings will help to develop new treatment strategies in CRC patients.

描述（由申请人提供）：结直肠癌（CRC）是美国与癌症相关死亡的第二大原因。预计2013年将大约有142,000例新病例和51,000例死亡。为了改善CRC患者的整体存活，需要更好地了解导致癌症进展和化学耐药性的分子事件。我们的实验室一直集中在阐明新型蛋白质磷酸酶家族的作用PHLPP（pH结构域亮氨酸重复蛋白蛋白磷酸酶）在抑制CRC的启动和进展中的作用。我们在理解PHLPP作为肿瘤抑制因子以及PHLPP调节的分子机制的功能重要性方面取得了重大进展。在这项拟议的研究中，我们将确定PHLPP损失对调节CRC中脂质代谢的影响。尽管癌症代谢研究的最新进展已开始阐明代谢变化如何支持癌细胞的生长和生存，但CRC中脂质代谢改变的调节和功能重要性仍然难以捉摸。该提议集中在一个新的假设上，即PHLPP-loss通过促进脂肪生成在推动CRC进展中起关键作用。在令人兴奋的最近发现中，我们证明了PHLPP表达的下调导致激活的SREBP1表达增加，SREBP1是脂质生物合成的关键激活剂。一致地，从PHLPP基因敲除小鼠中分离出的MEF细胞在分化为脂肪细胞的过程中具有增强的脂肪生成。此外，我们发现沉默的PHLPP表达会导致葡萄糖摄取，乳酸产生，krebs循环活性和三酰基甘油三酸酯在CRC细胞中的积累，这表明PHLPP在调节细胞代谢中的作用。推动这项研究的中心假设是，PHLPP通过负调节PI3K/AKT/MTOR途径来抑制脂肪生成起着至关重要的作用，而PHLPP表达的丧失促进了由于代谢重编程而促进CRC的进展。提出了以下特定目的：1）描述PHLPP调节CRC细胞中脂肪形成的分子机制。我们将执行稳定的同位素分辨代谢组学（SIRM）分析，以确定PHLPP-loss如何影响CRC细胞中的脂质代谢； 2）确定PHLPP介导的脂肪生成调节的功能重要性。我们将测试PHLPP损伤是否会导致CRC细胞对脂肪生成的改变，对代谢应激和化学疗法药物具有更大的耐药性； 3）定义PHLPP在抑制体内脂肪生成中的作用。 PHLPP损伤对调节脂质代谢的影响将使用遗传修饰的小鼠模型和患者衍生的异种移植模型确定。我们的研究结果将填补有关脂肪形成改变如何影响CRC患者预后和治疗功效的重要知识差距。最终，通过洞悉PHLPP介导的脂肪生成的机制，我们的发现将有助于制定CRC患者的新治疗策略。