Novel Role(s) of Nrf2 in the Growth of Post-Transplantation Cancer

Nrf2 在移植后癌症生长中的新作用

• 批准号: 9386736
• 负责人: Soumitro Pal
• 金额: $ 40.49万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386736
• 关键词: 1-Phosphatidylinositol 3-Kinase; Allografting; Antioxidants; Apoptosis; Apoptotic; Attenuated; Calcineurin inhibitor; Cancer cell line; Cell Cycle Progression; Down-Regulation; Drug usage; Effectiveness; Endothelial Cells; Equilibrium; Event; Expression Profiling; Goals; Growth; HGF gene; Immunosuppressive Agents; In Vitro; Kidney; Kidney Neoplasms; Kidney Transplantation; Lead; Ligands; MAP Kinase Gene; MAPK14 gene; MAPK3 gene; Malignant Neoplasms; Mediating; Modeling; Morphogenesis; Oncogenes; Organ Transplantation; Oxidation-Reduction; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Ras/Raf; Receptor Protein-Tyrosine Kinases; Regulation; Renal Cell Carcinoma; Renal carcinoma; Resistance; Role; Signal Transduction; Solid; Testing; Therapeutic immunosuppression; Tissues; Transcription Repressor/Corepressor; Transplant Recipients; Transplantation; Transplanted tissue; Xenograft Model; activating transcription factor; angiogenesis; cancer therapy; cancer transplantation; cell killing; chemotherapeutic agent; chemotherapy; design; heme oxygenase-1; in vivo; inhibitor/antagonist; knock-down; migration; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; overexpression; prevent; public health relevance; rapid growth; rho; targeted treatment; transcription factor; tumor; tumor growth; tumor xenograft; tumorigenesis

 DESCRIPTION (provided by applicant): There are limited treatment options for advanced renal cell carcinoma (RCC). Interestingly, kidney cancer is also a critical problem in organ transplant patients receiving immunosuppressive therapy, particularly with calcineurin inhibitors (CNIs). Thus, the accelerated rate of cancer in transplant recipients can serve as a unique model to understand the mechanism(s) of renal tumor growth. We discovered that in CNI-induced renal cancer, the Ras-Raf pathway is highly activated to promote over-expression of the anti-oxidant and cytoprotective molecule heme oxygenase-1 (HO-1). HO-1 mediates a rapid growth and survival of renal cancer cells, and it can lead to resistance against chemotherapeutic treatments. The apoptotic effects of commonly used drugs for renal cancer treatment were markedly enhanced upon HO-1 knockdown. We recently identified that the transcription factor Nrf2 is highly activated in RCC through the induction of Ras-Raf pathway, and it mediates HO-1 over-expression. One of the possible mechanism(s) for hyper activation of the Ras-Raf pathway in RCC is due to the signaling through upstream receptor tyrosine kinases (RTKs). The RTK c-MET is over-expressed in RCC; and in preliminary studies, we observed that the induction of c-MET activates the Ras pathway and induces Nrf2/HO-1. As discussed, kidney cancer is one of the most common cancers in patients having solid organ transplantation. Oncogenes, including ras, become activated during post-transplantation period. We have demonstrated that although CNIs are very good immunosuppressive agents to prolong allograft survival, they can promote a rapid progression of post-transplantation cancer; and CNI-induced tumors were associated with Ras/Raf-1/Nrf2 activation, HO-1 over-expression and angiogenesis. Interestingly, we also observed that the CNI treatment can promote an increased phosphorylation of c-MET; and thus c-MET can possibly be a critical molecule for CNI-induced and Ras-Nrf2-mediated renal tumor growth. Together, Nrf2 has a great potential to be considered as a novel therapeutic target in RCC. We hypothesize that targeting the c-MET-Ras-Nrf2 pathway and the inhibition of HO-1 will attenuate the growth, angiogenesis and progression of renal cancer (with importance to CNI-induced post-transplantation cancer), and it will significantly promote the tumor killing efficienc of chemotherapeutic agents. In our specific aims, we will study: 1) roles of CNI- and c- MET-induced pathway(s) in the regulation of Ras-mediated Nrf2 activation/stabilization in renal cancer cells (Aim-1); 2) role(s) of Nrf2 in regulating CNI- and c-MET-induced growth of renal cancer cells (Aim-2); and 3) roles of c-MET/Raf-1 and Nrf2 in CNI-induced renal cancer growth after organ transplantation in murine model; and to evaluate the expression of Nrf2 and HO-1 in renal tumor tissues from transplant and non-transplant patients (Aim-3). Together, our studies should identify the c-MET-Ras-Nrf2-HO-1 tumor-promoting pathway as a new and novel therapeutic target in RCC, with particular importance to CNI-induced post-transplantation cancer. It should lead to a paradigm shift for current therapies in renal cancer.

 描述（由申请人提供）：晚期肾细胞癌（RCC）的治疗选择有限。有趣的是，肾癌也是接受免疫抑制治疗的器官移植患者的关键问题，特别是使用钙调磷酸酶抑制剂（CNI）。因此，移植受者中癌症的加速速率可以作为理解肾肿瘤生长机制的独特模型。我们发现，在CNI诱导的肾癌中，Ras-Raf通路被高度激活，以促进抗氧化和细胞保护分子血红素加氧酶-1（HO-1）的过度表达。HO-1介导肾癌细胞的快速生长和存活，并且其可导致对化学治疗的抗性。常用的肾癌治疗药物的凋亡作用在HO-1敲低后显著增强。我们最近发现转录因子Nrf 2在肾细胞癌中通过诱导Ras-Raf通路被高度激活，并介导HO-1的过度表达。Ras-Raf通路在肾细胞癌中过度激活的可能机制之一是通过上游受体酪氨酸激酶（RTK）的信号传导。RTK c-MET在RCC中过表达;在初步研究中，我们观察到c-MET的诱导激活Ras通路并诱导Nrf 2/HO-1。如前所述，肾癌是实体器官移植患者最常见的癌症之一。癌基因，包括ras，在移植后期间被激活。我们已经证明，虽然CNI是非常好的免疫抑制剂，以延长同种异体移植物的生存，他们可以促进移植后癌症的快速进展;和CNI诱导的肿瘤与Ras/Raf-1/Nrf 2激活，HO-1过表达和血管生成。有趣的是，我们还观察到CNI治疗可以促进c-MET的磷酸化增加;因此c-MET可能是CNI诱导和Ras-Nrf 2介导的肾肿瘤生长的关键分子。总之，Nrf 2有很大的潜力被认为是RCC的新的治疗靶点。我们假设靶向c-MET-Ras-Nrf 2通路和抑制HO-1将减弱肾癌的生长、血管生成和进展（对CNI诱导的移植后癌症具有重要意义），并且将显著提高化疗药物的肿瘤杀伤效率。在我们的具体目标中，我们将研究：1）CNI-和c-MET-诱导的通路在肾癌细胞中Ras介导的Nrf 2活化/稳定的调节中的作用（Aim-1）; 2）Nrf 2在调节CNI-和c-MET-诱导的肾癌细胞生长中的作用（Aim-2）; 3）c-MET/Raf-1和Nrf 2在CNI诱导的小鼠器官移植后肾癌生长中的作用;并评估移植和非移植患者肾肿瘤组织中Nrf 2和HO-1的表达（Aim-3）。总之，我们的研究应该确定c-MET-Ras-Nrf 2-HO-1肿瘤促进途径作为RCC的新的和新颖的治疗靶点，对CNI诱导的移植后癌症特别重要。它应该导致目前肾癌治疗的范式转变。