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.

在美国，结直肠癌是癌症相关死亡的第二大原因。大致 预计2019年将有145,000例新病例和51,000例死亡；而这些死亡主要是由于 对可用的治疗方案反应不佳。更好地理解导致分子事件的 癌症进展和化疗耐药是提高癌症患者总体存活率所必需的。 我的实验室一直致力于阐明一种新的蛋白磷酸酶家族PHLPP的作用 (PH域富含亮氨酸重复蛋白磷酸酶)，抑制结肠癌的发生和发展。我们 在理解PHLPP作为肿瘤抑制因子的功能重要性方面取得了实质性进展 以及PHLPP调控的分子机制。这项研究的总体目标是进一步 发展对PHLPP介导的细胞应激反应调节的机械理解 细胞存活和肿瘤发生。在最近令人兴奋的发现中，我们证明了化疗诱导ER 应激促进PHLPP降解，PHLPP缺失通过上调提供生存优势 EIF2α/ATF4介导的信号转导。此外，我们发现PHLPP的下调促进了线粒体 通过调节Drp1的磷酸化来进行分裂。总而言之，推动这项拟议研究的中心假设是 PHLPP在CRC中起着重要的应力传感器作用，在这种传感器中，细胞应力信号触发PHLPP的降解 以促进细胞存活和肿瘤形成。建议的具体目标如下：1)划定 PHLPP调控eIF2α/ATF4信号的分子机制。我们将确定是否 自噬导致PHLPP下调使结肠癌细胞对化疗药物产生耐药性 2)确定PHLPP介导的线粒体动力学调节的功能重要性。 我们将验证PHLPP在调节线粒体动力学方面发挥重要作用的假设 增强DRp1活性以应对促炎应激信号；以及3)确定 线粒体动力学在协同PHLPP-Lost促进体内肿瘤发生中的作用。我们将使用Drp1 和PHLPP基因敲除小鼠来确定PHLPP和Drp1在调节结肠上的功能相互作用 肿瘤在体内的发生。我们提议的研究集中在一个新的假设上，即PHLPP-Lost在 在细胞应激信号下游协调多种有利于生存的反应中发挥关键作用 肿瘤发生学。我们的研究将填补关于线粒体动力学改变如何起作用的重要知识空白 与结肠癌的肿瘤发生和发展有关。最终，通过提供对PHLPP的机械性见解- 依赖于应激反应的调节，我们的发现将有助于确定新的治疗方案并更好地预测 基于PHLPP状态的癌症患者化疗药物的疗效。