Protein Kinase C and GSTP1 interactions in glioma drug resistance

蛋白激酶 C 和 GSTP1 在神经胶质瘤耐药中的相互作用

• 批准号: 7534911
• 负责人: FRANCIS ALI-OSMAN
• 金额: $ 31.67万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534911
• 关键词: Amino Acids; Antineoplastic Agents; Apoptotic; Binding; Brain; Brain Neoplasms; Cell Line; Cells; Data; Development; Disease; Down-Regulation; Drug resistance; Failure; Family; Genetic; Glioma; Glutathione S-Transferase; Goals; Growth; Half-Life; Human; In Vitro; JNK-activating protein kinase; Knowledge; Laboratories; Lead; MAPK8 gene; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of central nervous system; Mass Spectrum Analysis; Mediating; Metabolic; Molecular; N-terminal; Nuclear; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Play; Protein Isoforms; Protein Kinase C; Protein Overexpression; Protein-Serine-Threonine Kinases; Proteins; Public Health; Reporting; Research; Resistance; Role; Seminal; Serine; Signal Transduction; Signaling Protein; Site; Site-Directed Mutagenesis; Specimen; Testing; Therapeutic; Threonine; Toxic effect; Variant; base; chemotherapeutic agent; chemotherapy; drug sensitivity; in vivo; inhibitor/antagonist; insight; novel therapeutics; prognostic; response; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Current chemotherapy of malignant tumors of the central nervous system rarely results in significant long-term responses. Two major factors underlying this poor therapeutic outcome are the intrinsic resistance of brain tumors to chemotherapy and the poor selectivity and high toxicity of current treatments. The development of more tumor-specific therapies and therapeutic strategies for brain tumors, however, will require knowledge of the molecular mechanisms and abnormalities that drive the growth and therapeutic response of the tumors. This project is built on recent findings in our laboratory on the crosstalk between a major Phase II drug metabolizing and cell signaling protein, the glutathione S-transferase P1 (GSTP1) and the serine/threonine protein kinase, PKC. These two proteins are highly expressed in many human tumors, including, those of the brain and the high expression has been associated with rapid progression and failure of chemotherapy in several of these malignancies. In gliomas, high GSTP1 expression and its nuclear localization have been associated with poor patient survival. Similarly, high PKC activity is frequently observed in malignant gliomas and has been associated with glioma drug resistance. Recently, we reported that the GSTP1 protein is a, heretofore, unrecognized downstream target of PKC and undergoes phosphorylation by PKC, resulting in a significant enhancement of its metabolic activity. Our preliminary data suggest that these two pathways can function interactively to increase the resistance of glioma cells to anticancer agents. Our goal in this application is to investigate these seminal findings for their prognostic significance and as a basis for developing more effective therapy for malignant gliomas. The hypothesis to be tested is that phosphorylation of the GSTP1 protein by the PKC family of serine/threonine kinases, will enhance the ability of the GSTP1 protein to metabolize and inactivate chemotherapeutic agents and to inhibit downstream jun N-terminal kinase signaling, thus, leading to more aggressive growth and increased drug resistance of gliomas. We postulate that PKC inhibition/downregulation, alone and/or in combination with GSTP1 downregulation, will have significant antiglioma efficacy and increase glioma sensitivity to chemotherapy. The proposed research will provide important insights into the cellular pathways mediated by this newly identified crosstalk between GSTP1 and PKC in gliomas and the role that this interaction plays in tumor growth and therapeutic response in gliomas. The results are likely to lead to novel therapeutic strategies for malignant gliomas, particularly those characterized by high GSTP1 expression and elevated or highly activated PKCs. Malignant gliomas are among the most therapeutically intractable tumors. In this application, we propose research to better characterize a newly identified crosstalk between two proteins, glutathione S-transferase P1 (GSTP1) a major Phase II drug metabolizing and cell signaling protein, and the serine/threonine protein kinase, PKC, in which the latter phosphorylates and increases the catalytic activity of the former. Both proteins are highly expressed in malignant gliomas and are associated with rapid progression and failure of chemotherapy. PUBLIC HEALTH RELEVANCE We characterize the phosphorylation of GSTP1 by PKC and examine how the modulation of the phosphorylation alters the drug sensitivity of gliomas in vitro and in vivo. The results are likely to lead to novel therapeutic strategies for malignant gliomas, particularly; those characterized by high GSTP1 expression and elevated or highly activated PKCs.

描述（由申请人提供）：目前中枢神经系统恶性肿瘤的化疗很少产生显着的长期反应。这种不良治疗结果的两个主要因素是脑肿瘤对化疗的内在抵抗力以及当前治疗的选择性差和高毒性。然而，开发针对脑肿瘤的更多肿瘤特异性疗法和治疗策略将需要了解驱动肿瘤生长和治疗反应的分子机制和异常。该项目基于我们实验室最近关于主要 II 期药物代谢和细胞信号蛋白、谷胱甘肽 S-转移酶 P1 (GSTP1) 和丝氨酸/苏氨酸蛋白激酶 PKC 之间串扰的发现。这两种蛋白质在许多人类肿瘤中高表达，包括脑肿瘤，并且高表达与其中几种恶性肿瘤的快速进展和化疗失败有关。在神经胶质瘤中，GSTP1 的高表达及其核定位与患者生存率较差有关。同样，在恶性神经胶质瘤中经常观察到高 PKC 活性，并且与神经胶质瘤耐药性相关。最近，我们报道GSTP1蛋白是迄今为止未被识别的PKC下游靶标，并被PKC磷酸化，导致其代谢活性显着增强。我们的初步数据表明，这两条途径可以相互作用，增加神经胶质瘤细胞对抗癌药物的抵抗力。我们在本申请中的目标是研究这些开创性的发现及其预后意义，并作为开发更有效的恶性胶质瘤治疗方法的基础。待测试的假设是，丝氨酸/苏氨酸激酶的 PKC 家族对 GSTP1 蛋白的磷酸化将增强 GSTP1 蛋白代谢和灭活化疗药物的能力，并抑制下游 jun N 端激酶信号传导，从而导致神经胶质瘤更具侵袭性生长和耐药性增加。我们假设 PKC 抑制/下调，单独和/或与 GSTP1 下调相结合，将具有显着的抗神经胶质瘤功效，并增加神经胶质瘤对化疗的敏感性。拟议的研究将为神经胶质瘤中新发现的 GSTP1 和 PKC 之间的串扰介导的细胞通路以及这种相互作用在神经胶质瘤的肿瘤生长和治疗反应中所起的作用提供重要的见解。这些结果可能会为恶性神经胶质瘤带来新的治疗策略，特别是那些以 GSTP1 高表达和 PKC 升高或高度激活为特征的恶性神经胶质瘤。恶性神经胶质瘤是治疗上最难治疗的肿瘤之一。在本申请中，我们提出研究更好地表征两种蛋白质之间新发现的串扰，即谷胱甘肽 S 转移酶 P1 (GSTP1)（一种主要的 II 期药物代谢和细胞信号传导蛋白）和丝氨酸/苏氨酸蛋白激酶 PKC，其中后者磷酸化并增加前者的催化活性。这两种蛋白在恶性神经胶质瘤中高度表达，并与化疗的快速进展和失败相关。公共健康相关性 我们表征了 PKC 对 GSTP1 的磷酸化，并研究了磷酸化的调节如何改变体外和体内神经胶质瘤的药物敏感性。研究结果可能会为恶性神经胶质瘤带来新的治疗策略，特别是；其特征是 GSTP1 高表达和 PKC 升高或高度激活。