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

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 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.