Novel Role of Honokiol in Preventing Cancer during Immune Suppression

 说明(申请人提供)：免疫抑制剂，如钙调神经磷酸酶抑制剂(CNI)，对于治疗各种炎症性和自身免疫性疾病以及预防移植患者的同种异体排斥反应是必不可少的。然而，在接受免疫抑制治疗的患者中，癌症的发展、复发和快速进展是一个主要问题。肾癌是接受CNI治疗的患者最常见的癌症之一，特别是在接受实体器官移植的患者中。Ras-Raf通路在肾癌细胞中经常被过度激活，特别是通过表皮生长因子受体(EGFR)的信号转导。我们已经证明，CNI治疗可以直接激活Ras-Raf致癌途径，通过细胞保护分子血红素加氧酶-1(HO-1)的过度表达促进肾癌的快速进展。激活的Ras-Raf-ERK途径通过转录因子Nrf2诱导HO-1；HO-1通过下调细胞凋亡和诱导血管生成促进肾癌细胞的存活。在HO-1基因敲除后，雷帕霉素和索拉非尼这两种治疗肾癌的常用药物的细胞凋亡作用明显增强。因此，探索一种既能维持免疫抑制又能防止肿瘤生长的机制(S)至关重要。和厚朴酚是从厚朴中分离得到的天然产物，是一种具有抗炎、抗氧化、促细胞凋亡和化学预防作用的药物。在我们的初步研究中，我们发现和厚朴酚可以有效地下调CNI诱导的Ras-Raf途径的激活。我们还首次证明和厚朴酚通过抑制CNI诱导的HO-1的过度表达来促进细胞凋亡，HO-1在RAS介导的肾癌细胞存活中起主要作用。目前，在接受免疫抑制治疗的患者中预防癌症的药物很少，而且大多数药物都与显著的副作用和毒副作用有关。因此，和厚朴酚有很大的潜力作为一种新的药物来预防免疫抑制患者的癌症生长。我们假设和厚朴酚抑制CNI的促癌作用，但保留其免疫抑制功能，以预防免疫紊乱和同种异体移植排斥反应。在我们的具体目标中，我们将研究：1)和厚朴酚下调CNI诱导和RAS介导的NRF2-HO-1激活的机制(S)；以及和厚朴酚如何阻止CNI诱导的肾癌生长和进展途径(AIM-1)；以及2)和厚朴酚在预防器官移植后CNI诱导和RAS-HO-1介导的肾癌生长中的作用(AIM-2)。总之，我们的研究应该会导致范式的转变，因为在CNI治疗中加入和厚朴酚可以减弱RAS-Raf诱导的CNI促癌途径，而不会影响其所需的免疫抑制功能。

 DESCRIPTION (provided by applicant): The immunosuppressive agents, like calcineurin inhibitors (CNI), are essential for the treatment of various inflammatory and autoimmune disorders, and also for the prevention of allograft rejection in transplant patients. However, the development, recurrence, and a rapid progression of cancer is a major problem in patients receiving immunosuppressive therapy. Kidney cancer is one of the most common cancers in CNI-treated patients, particularly in patients receiving solid organ transplants. The Ras-Raf pathway is often hyper- activated in renal cancer cells, particularly by the signaling through the epidermal growth factor receptor (EGFR). We have demonstrated that CNI treatment can directly activate the Ras-Raf oncogenic pathway to promote a rapid progression of renal cancer through the over-expression of the cytoprotective molecule heme oxygenase-1 (HO-1). The activated Ras-Raf-ERK pathway induces HO-1 through the transcription factor Nrf2; and HO-1 promotes the survival of renal cancer cells through the down-regulation of apoptosis and induction of angiogenesis. The apoptotic effects of rapamycin (RAPA) and sorafenib, two commonly used drugs for renal cancer treatment, were markedly enhanced upon HO-1 knockdown. Thus, it is critical to explore a mechanism(s) by which we can not only sustain immune suppression but also prevent cancer growth. Honokiol, a natural product originally isolated from Magnolia obovata, is a promising agent for mediating anti- inflammatory, anti-oxidant, pro-apoptotic and chemopreventive functions. In our preliminary studies, we have found that Honokiol can effectively down-regulate CNI-induced activation of the Ras-Raf pathway. We also demonstrate for the first time that Honokiol promotes apoptosis by inhibiting CNI-induced over-expression of HO-1, which plays a major role in Ras-mediated survival of renal cancer cells. Currently, there are very few agents to prevent cancer in patients undergoing immunosuppressive therapy; and most of these agents are associated with significant side effects and toxicities. Thus, it appears that Honokiol can have great potential to be used as a novel agent to prevent cancer growth in immunosuppressed patients. We hypothesize that Honokiol inhibits the cancer-promoting effects of CNI but retains its immunosuppressive functions for the prevention of immune disorders and allograft rejection. In our specific aims, we will study: 1) the mechanism(s) by which Honokiol can down-regulate CNI-induced and Ras-mediated activation of Nrf2-HO-1; and how Honokiol can prevent CNI-induced pathways for renal cancer growth and progression (Aim-1); and 2) the role of Honokiol in preventing CNI-induced and Ras-HO-1-mediated renal cancer growth after organ transplantation (Aim-2). Together, our studies should lead to a paradigm shift as the addition of Honokiol to CNI treatment can attenuate the Ras-Raf-induced cancer-promoting pathways of CNI, without affecting its required immunosuppressive functions.