Protein Kinase C Signaling Mechanisms in Cancer

癌症中的蛋白激酶 C 信号传导机制

• 批准号: 7843610
• 负责人: Alan P. Fields
• 金额: $ 43.81万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-02 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7843610
• 关键词: Address; Anchorage-Independent Growth; Animal Model; Aurothiomalate; Binding; Cancer Biology; Cancer Etiology; Cancer Model; Cancer Patient; Cessation of life; Clinical; Clinical Treatment; Complex; Cytoplasm; Data; Development; Drug Delivery Systems; Epithelium; Family; Funding; Gene Amplification; Genes; Genetic; Goals; Growth; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Human; In Vitro; Knock-out; Lateral; Link; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mediating; Mediator of activation protein; Modeling; Mus; Mutate; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Outcome; Phase I Clinical Trials; Phospho-Specific Antibodies; Phosphorylation; Phosphorylation Site; Play; Preclinical Drug Evaluation; Prognostic Marker; Protein Kinase; Protein Kinase C; Proteins; Publishing; Regulation; Role; Signal Transduction; Site; Testing; Transgenic Mice; Transgenic Organisms; Translating; Tumorigenicity; United States; base; cancer cell; cell transformation; citrate carrier; design; in vivo; insight; lung carcinogenesis; lung tumorigenesis; mouse model; new therapeutic target; novel; overexpression; pre-clinical; prognostic; protein complex; public health relevance; rho; therapeutic development; therapeutic target; treatment strategy; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): The long-term goals of this competing renewal are to elucidate protein kinase C (PKC) signaling mechanisms that contribute to cancer and translate these mechanistic insights into better prognostic and treatment strategies. During the current funding period, we identified PKC? as a human oncogene in non-small cell lung cancer (NSCLC), the number one cancer killer in the United States. PKC? drives anchorage-independent growth and invasion in NSCLC cells by forming a protein-protein complex with the adaptor molecule Par6. The PKC?-Par6 complex activates the Rho family GTPase Rac1 to induce expression of matrix metalloproteinase10 (MMP10). MMP10 is a critical effector of the PKC9-Par6-Rac1 signaling axis and is required for anchorage-independent growth and invasion in vitro. These mechanistic studies informed the design of a rational drug screening strategy which identified the first PKC?-targeted drug, aurothiomalate (ATM) which is currently in Phase I clinical trials for treatment of lung cancer. In this application, we will address three major aspects of oncogenic PKC? signaling. First, we will determine how PKC? activates Rac1. Preliminary data indicate that the Rac-GEF Ect2 regulates Rac1, is required for NSCLC cell transformation, associates with the oncogenic PKC?-Par6 complex and is phosphorylated by PKC?. In Specific Aim 1 we will test the hypothesis that Ect2 is a critical effector of oncogenic PKC? and that PKC?-mediated phosphorylation regulates the oncogenic activity of Ect2. Completion of this aim will provide a novel functional link between Ect2 and PKC?. Second, we will assess whether the oncogenic PKC? signaling axis we defined in NSCLC cells in vitro is required for NSCLC tumor growth and metastasis in vivo. In Specific Aim 2, we will test the hypothesis that the PKC?-Par6-Ect2-Rac1-MMP10 signaling axis is necessary for NSCLC tumor growth and metastasis in vivo. We will establish novel orthotopic NSCLC tumor models to assess the role of key components of this signaling axis in vivo. Third, we will determine whether MMP10 is required for lung carcinogenesis in vivo. Preliminary data demonstrate that PKC? is required for lung carcinogenesis induced by oncogenic K-ras in vivo. In Specific Aim 3 we will test the hypothesis that MMP10 is a critical effector of PKC? in K-ras-mediated lung carcinogenesis in vivo. We will establish novel transgenic mouse models to assess whether MMP10 can drive spontaneous lung carcinogenesis, exacerbate K-ras-mediated lung carcinogenesis and/or restore K-ras-mediated lung carcinogenesis in mice lacking PKC?. Completion of these aims will provide critical new insight into oncogenic PKC? signaling, establish the role of Ect2 in NSCLC, assess the importance of oncogenic PKC? signaling in relevant preclinical NSCLC models in vivo, and determine if MMP10 is a critical mediator of lung carcinogenesis in vivo. These studies will likely reveal Ect2 and MMP10 as novel therapeutic targets for development of therapeutics for treatment of lung cancer. PUBLIC HEALTH RELEVANCE: Lung cancer is the number one cause of cancer death in the United States. Protein kinase C? (PKC?) is an oncogene, prognostic marker and therapeutic target in lung cancer. This project will elucidate the PKC? signaling mechanisms that drive lung cancer growth and assess the importance of PKC? signaling in lung cancer development, progression and spread in pre-clinical animal models in vivo.

描述（由申请人提供）：这种竞争更新的长期目标是阐明有助于癌症并将这些机械洞察力转化为更好的预后和治疗策略的蛋白激酶C（PKC）信号传导机制。在当前的资金期间，我们确定了PKC？作为非小细胞肺癌（NSCLC）中的人类癌基因，这是美国排名第一的癌症杀手。 PKC？通过与适配器分子PAR6形成蛋白质 - 蛋白质复合物，可以驱动非锚定依赖性的生长和侵袭NSCLC细胞。 PKC？-Par6复合物激活Rho家族GTPase Rac1，以诱导基质金属蛋白酶10（MMP10）的表达。 MMP10是PKC9-PAR6-RAC1信号轴的关键效应子，是锚定非依赖性生长和体外侵袭所必需的。这些机械研究为一项合理的药物筛查策略的设计提供了信息，该策略鉴定了第一个PKC？the-targe的药物，Aurothiomalate（ATM），该药物目前正在I期治疗肺癌治疗的I期临床试验中。在此应用程序中，我们将解决致癌PKC的三个主要方面？信号。首先，我们将确定PKC如何？激活Rac1。初步数据表明，NSCLC细胞转化所需的RAC-GEF ECT2调节Rac1，与致癌PKC？-Par6复合物相关，并且是由PKC磷酸化的。在特定目标1中，我们将测试ECT2是致癌PKC的关键效应因子的假设？ PKC？介导的磷酸化调节ECT2的致癌活性。此目标的完成将提供ECT2和PKC之间的新功能联系。其次，我们将评估致癌性PKC是否？我们在NSCLC细胞中定义的信号轴是NSCLC肿瘤生长和体内转移所必需的。在特定的目标2中，我们将测试以下假设：PKC？-Par6-ect2-Rac1-MMP10信号轴是NSCLC肿瘤生长和体内转移所必需的。我们将建立新型的原位NSCLC肿瘤模型，以评估体内信号轴关键组件的作用。第三，我们将确定体内肺癌发生是否需要MMP10。初步数据证明了PKC？是由体内致癌K-Ras诱导的肺癌发生所必需的。在特定目标3中，我们将测试MMP10是PKC的关键效应因子的假设？在K-RAS介导的体内肺癌发生中。我们将建立新型的转基因小鼠模型，以评估MMP10是否可以驱动自发的肺癌发生，加剧K-RAS介导的肺癌发生和/或恢复缺乏PKC的小鼠的K-RAS介导的肺癌发生。这些目标的完成将为致癌PKC提供重要的新见解吗？信号传导，确定ECT2在NSCLC中的作用，评估致癌PKC的重要性？相关临床前NSCLC模型中的信号传导，并确定MMP10是否是体内肺癌发生的关键介体。这些研究可能会揭示ECT2和MMP10是用于治疗肺癌治疗的新型治疗靶标。 公共卫生相关性：肺癌是美国癌症死亡的第一大原因。蛋白激酶C？ （PKC？）肺癌中的癌基因，预后标记和治疗靶标。这个项目将阐明PKC？促进肺癌生长并评估PKC重要性的信号传导机制？肺癌发展，进展和体内临床动物模型中的信号传导。