Protective role of Honokiol in preventing c-Met-induced post-transplantation cancer

项目总结 癌症是免疫抑制患者的一个关键问题，尤其是接受器官移植的患者； 肾/肾癌是这些患者的主要癌症之一。直接致瘤途径(独立于 免疫逃逸机制)在移植后癌症的发生发展中起关键作用。C-Met IS 一种受体酪氨酸激酶，在肾癌中显著过度表达。它可以通过以下方式诱导肿瘤生长 通过调节细胞保护来调节氧化还原途径、血管生成和凋亡事件 分子NRF2和血红素加氧酶-1(HO-1)。NRF2/HO-1已被证明调节细胞的氧化还原状态 癌细胞(通过解毒活性氧物种，ROS)，并保护它们免受化疗的影响 药物诱导的细胞凋亡。有趣的是，c-Met-Nrf2-HO-1通路在休克后也被激活。 移植物移植期。MTOR抑制剂Rapa用于移植患者，以防止器官排斥反应；以及 有趣的是，它还具有抗血管生成的潜力，并用于治疗肾癌。然而， RAPA的反应是短暂的，大多数患者最终产生了抵抗力。延长的RAPA 治疗不能通过解除抑制来预防由于Akt激活而导致的移植后癌症 循环播放。因此，需要开发新的肾癌治疗方法。和厚朴酚(C18H18O2)--小说 这种药物(从木兰花中分离出来)正在临床前模型中进行抗肿瘤潜能测试。 此外，和厚朴酚还具有抗炎作用，可用于移植治疗 患者要维持他们的免疫抑制。在初步研究中，我们观察到和厚朴酚治疗 能下调c-Met诱导的RAS激活(与Akt-mTor有串扰)并抑制Nrf2/HO-1 肾癌细胞。总而言之，和厚朴酚似乎是一种很有前途的治疗c-Met诱导的后遗症的药物。 移植肾癌。我们假设和厚朴酚和mTOR的联合治疗 RAPA抑制剂不仅能延长移植物存活时间，还能阻止c-Met诱导和Nrf2/HO-1介导的移植肾存活 移植后肾癌。在具体目标上，我们将：1)研究和厚朴酚的作用机理(S)。 Nrf2/HO失稳/失活抑制c-Met诱导的肾癌细胞致癌信号 1和氧化还原途径的调节(AIM-1)，2)研究和厚朴酚如何在mTOR存在的情况下处理 RAPA抑制剂在体外可下调c-Met诱导的肾癌生长和进展途径， 在肿瘤异种移植模型(AIM-2)中，以及3)检测和厚朴酚和RAPA联合治疗对 新型小鼠预防早期肾肿瘤发生及c-Met诱导的移植后肾癌 模型(AIM-3)。我们的研究应该导致范式的转变，以确定一种新的联合疗法 和厚朴酚可延长同种异体移植物存活以及预防c-Met诱导的移植后癌症。

PROJECT SUMMARY Cancer is a critical problem in immunosuppressed patients, particularly, who receive organ transplants; and kidney/renal cancer is one of the major cancers in these patients. Direct tumorigenic pathways (independent of immune escape mechanism) can play crucial roles in the development of post-transplantation cancer. c-Met is a receptor tyrosine kinase, which is significantly over-expressed in renal cancer. It can induce tumor growth by modulating the redox pathway, angiogenesis and apoptotic events, through the regulation of cytoprotective molecules Nrf2 and heme oxygenase-1 (HO-1). Nrf2/HO-1 has been shown to modulate the redox state of cancer cells (by detoxification of reactive oxygen species, ROS), and to protect them from chemotherapeutic drug-induced apoptosis. Interestingly, the c-Met-Nrf2-HO-1 pathway is also activated during the post- transplantation period. The mTOR inhibitor RAPA is used in transplant patients to prevent organ rejection; and interestingly, it also has anti-angiogenic potential, and is used for the treatment of renal cancer. However, the RAPA responses are short lived, and most of the patients finally develop resistance. Prolonged RAPA treatment cannot prevent post-transplantation cancer due to the activation of Akt by relieving the inhibitory loop. Thus, new therapeutic approach needs to be developed for kidney cancer. Honokiol (C18H18O2), a novel agent (isolated from Magnolia obovata), is being tested in pre-clinical models for its anti-tumorigenic potential. In addition, Honokiol also has anti-inflammatory property, which can be utilized for the treatment of transplant patients to sustain their immune suppression. In preliminary studies, we have observed that Honokiol treatment can down-regulate c-Met-induced Ras activation (having cross-talk with Akt-mTOR) and inhibit Nrf2/HO-1 in renal cancer cells. Together, Honokiol appears to be a promising therapeutic agent for c-Met-induced post- transplantation renal cancer. We hypothesize that a combination therapy using Honokiol and the mTOR inhibitor RAPA will not only prolong allograft survival, but also prevent c-Met-induced and Nrf2/HO-1-mediated post-transplantation renal cancer. In the specific aims, we will: 1) study the mechanism(s) by which Honokiol inhibits c-Met-induced tumorigenic signals in renal cancer cells through destabilization/inactivation of Nrf2/HO- 1 and regulation of the redox pathway (Aim-1), 2) examine how Honokiol treatment in the presence of mTOR inhibitor RAPA can down-regulate c-Met-induced pathways for renal cancer growth and progression in vitro, and in a tumor xenograft model (Aim-2), and 3) test the effect of Honokiol and RAPA combination therapy in preventing early renal tumorigenesis and c-Met-induced post-transplantation renal cancer using novel murine models (Aim-3). Our studies should lead to a paradigm shift to identify a novel combination therapy with Honokiol to prolong allograft survival as well as to prevent c-Met-induced post-transplantation cancer.