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: 8288923
• 负责人: Alan P. Fields
• 金额: $ 41.5万
• 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 2013-07-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288923
• 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; Health; 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; design; in vivo; insight; lung carcinogenesis; lung tumorigenesis; mouse model; new therapeutic target; novel; overexpression; pre-clinical; prognostic; protein complex; 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）：这一竞争性更新的长期目标是阐明导致癌症的蛋白激酶 C (PKC) 信号传导机制，并将这些机制见解转化为更好的预后和治疗策略。在当前资助期间，我们确定了 PKC？作为美国头号癌症杀手非小细胞肺癌 (NSCLC) 的人类癌基因。 PKC？通过与接头分子 Par6 形成蛋白质-蛋白质复合物，驱动 NSCLC 细胞的贴壁依赖性生长和侵袭。 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，是体外贴壁依赖性生长和侵袭所必需的。这些机制研究为合理的药物筛选策略的设计提供了信息，该策略确定了第一个 PKC? 靶向药物金硫苹果酸 (ATM)，该药物目前正处于治疗肺癌的 I 期临床试验中。在此应用中，我们将解决致癌 PKC 的三个主要方面？发信号。首先，我们将如何确定PKC？激活 Rac1。初步数据表明，Rac-GEF Ect2 调节 Rac1，是 NSCLC 细胞转化所必需的，与致癌 PKC?-Par6 复合物结合，并被 PKC? 磷酸化。在具体目标 1 中，我们将检验以下假设：Ect2 是致癌 PKC 的关键效应子？ PKC介导的磷酸化调节Ect2的致癌活性。这一目标的完成将为 Ect2 和 PKC? 之间提供一种新颖的功能联系。其次，我们会评估PKC是否致癌？我们在体外 NSCLC 细胞中定义的信号轴是 NSCLC 肿瘤体内生长和转移所必需的。在具体目标 2 中，我们将检验以下假设：PKC?-Par6-Ect2-Rac1-MMP10 信号轴对于 NSCLC 肿瘤体内生长和转移是必需的。我们将建立新型原位非小细胞肺癌肿瘤模型，以评估该信号轴关键成分在体内的作用。第三，我们将确定MMP10是否是体内肺癌发生所必需的。初步数据表明PKC？是体内致癌 K-ras 诱导肺癌发生所必需的。在特定目标 3 中，我们将检验 MMP10 是 PKC 关键效应子的假设？体内 K-ras 介导的肺癌发生。我们将建立新的转基因小鼠模型来评估MMP10是否可以驱动自发性肺癌发生、加剧K-ras介导的肺癌发生和/或在缺乏PKC的小鼠中恢复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？信号传导、确定 Ect2 在 NSCLC 中的作用、评估致癌 PKC 的重要性？体内相关临床前 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质。这些研究可能会揭示 Ect2 和 MMP10 作为开发肺癌疗法的新治疗靶点。 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？）是肺癌的癌基因、预后标志物和治疗靶点。这个项目将阐明PKC？驱动肺癌生长的信号机制并评估 PKC 的重要性？临床前动物模型体内肺癌发生、进展和扩散中的信号传导。