The Role of PHLPP in Colon Cancer

PHLPP 在结肠癌中的作用

• 批准号: 10400230
• 负责人: Tianyan Gao
• 金额: $ 38.96万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400230
• 关键词: Automobile Driving; Autophagocytosis; Cancer Etiology; Cancer Patient; Cell Death; Cell Proliferation; Cell Survival; Cells; Cellular Stress; Cellular Stress Response; Cessation of life; Chemoresistance; Collaborations; Colon Carcinoma; Colorectal Cancer; Development; Disease; Down-Regulation; Effectiveness; Ensure; Epithelial Cells; Equilibrium; Event; Funding; Grant; HK2 gene; Inflammation; Integrins; Intestines; Knockout Mice; Knowledge; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Oncogenic; Organism; PH Domain; Pathway interactions; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Play; Protein Dephosphorylation; Protein Family; Protein Kinase; Protein phosphatase; Proto-Oncogene Proteins c-akt; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Stress; Supporting Cell; Testing; Tumor Suppressor Proteins; United States; base; biological adaptation to stress; cancer cell; cancer initiation; cancer survival; cancer type; cell growth regulation; cell motility; chemotherapy; colon tumorigenesis; coping mechanism; endoplasmic reticulum stress; improved; in vivo; insight; leucine-rich repeat protein; mitochondrial autophagy; mortality; mouse model; multicatalytic endopeptidase complex; novel; protein expression; response; sensor; success; tumor initiation; tumor metabolism; tumor progression; tumorigenesis

Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately 145,000 new cases and 51,000 deaths are predicted for the year 2019; and this mortality is predominantly due to poor responses to available treatment options. A better understanding of the molecular events leading to cancer progression and chemoresistance is needed in order to improve the overall survival of cancer patients. My 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 colon cancer 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. The overall objective of this study is to further develop a mechanistic understanding of PHLPP-mediated regulation of cellular stress response in supporting cell survival and tumorigenesis. In exciting recent findings, we demonstrated that chemotherapy-induced ER stress promotes PHLPP degradation and PHLPP-loss provides a survival advantage by upregulating eIF2α/ATF4-mediated signaling. In addition, we found that downregulation of PHLPP promotes mitochondrial fission by regulating Drp1 phosphorylation. Collectively, the central hypothesis driving this proposed study is that PHLPP serves an essential stress sensor in CRC, in which cellular stress signals trigger PHLPP degradation to promote cell survival and tumorigenesis. The following specific aims are proposed: 1) to delineate the molecular mechanism underlying PHLPP-mediated regulation of eIF2α/ATF4 signaling. We will determine if downregulation of PHLPP renders colon cancer cells resistant to chemotherapy drugs as a result of autophagy activation; 2) to determine the functional importance of PHLPP-mediated regulation of mitochondrial dynamics. We will test the hypothesis that PHLPP plays an important role in regulating mitochondrial dynamics by enhancing Drp1 activity in order to cope with proinflammatory stress signals; and 3) to define the role of mitochondrial dynamics in cooperating with PHLPP-loss to promote tumorigenesis in vivo. We will utilize Drp1 and PHLPP knockout mice to determine the function interaction between PHLPP and Drp1 on regulating colon cancer tumorigenesis in vivo. Our proposed study centers on a novel hypothesis that that PHLPP-loss plays a pivotal role in orchestrating multiple pro-survival responses downstream of cellular stress signals to promote tumorigenesis. Our study will fill an important knowledge gap on how altered mitochondrial dynamics contributes to tumor initiation and progression in colon cancer. Ultimately, by providing mechanistic insights into PHLPP- dependent regulation of stress response, our findings will help identify new treatment options and better predict the effectiveness of chemotherapy agents based on PHLPP status in cancer patients.

结直肠癌是美国与癌症相关死亡的第二大原因。大约 预计2019年将有145,000例新病例和51,000例死亡；这种死亡率主要是应得的 对可用治疗方案的反应不佳。更好地了解导致的分子事件 为了改善癌症患者的总体存活，需要癌症的进展和化学抗性。 我的实验室一直集中在阐明新型蛋白质磷酸酶家族PHLPP家族的作用上 （pH结构域富含亮氨酸的重复蛋白磷酸酶），抑制结肠癌的启动和进展。我们 在理解PHLPP作为肿瘤抑制器的功能重要性方面取得了重大进展 以及PHLPP调控的基础机制。这项研究的总体目的是进一步 在支持中对PHLPP介导的细胞应力反应调节的机械理解 细胞存活和肿瘤发生。在令人兴奋的最近发现中，我们证明了化学疗法诱导的ER 压力会促进PHLPP降解和PHLPP损失，从而通过上调可提供生存优势 EIF2α/ATF4介导的信号传导。此外，我们发现PHLPP的下调促进了线粒体 通过控制DRP1磷酸化裂变。总的来说，推动这项研究的研究的中心假设是 PHLPP在CRC中提供了必不可少的应力传感器，其中细胞应力信号触发PHLPP降解 促进细胞存活和肿瘤发生。提出了以下特定目标：1）描述 PHLPP介导的EIF2α/ATF4信号的调节的分子机制。我们将确定是否 PHLPP的下调使结肠癌细胞由于自噬而抗化疗药物 激活; 2）确定PHLPP介导的线粒体动力学调节的功能重要性。 我们将检验以下假设，即PHLPP在通过指导线粒体动力学中起重要作用 增强DRP1活性以应对促炎应力信号； 3）定义 线粒体动力学与pHLPP损伤合作以促进体内肿瘤发生。我们将利用DRP1 和PHLPP敲除小鼠，以确定PHLPP和DRP1之间的功能相互作用 体内癌症肿瘤发生。我们提出的研究集中于一个新的假设，即PHLPP损失扮演 在编排细胞应力信号下游的多个促生物源反应中的关键作用以促进 肿瘤发生。我们的研究将填补有关线粒体动力学改变的重要知识差距 结肠癌的肿瘤启动和进展。最终，通过向PHLPP提供机械见解 - 依赖压力反应的调节，我们的发现将有助于确定新的治疗方案，并更好地预测 癌症患者基于PHLPP状态的化学疗法疗法的有效性。