Organ transplantation is considered to be the best treatment option for most of the patients having a dysfunctional organ;it provides them a long and healthy lifespan. However, the development/recurrence of cancer is a major and critical problem during post-transplantation period. Renal cancer is one of the major types of cancers in transplant patients. Interestingly, the immunosuppressive agents used in transplant recipients to prevent organ rejection can play a vital role in tumor progression. It has been observed that transplant patients receiving the mTOR inhibitor rapamycin (RAPA) do not develop cancer at the same rate as those receiving other immunosuppressive agents such as calcineurin inhibitors (CNI). We have defined a novel mechanism by which CNIs can activate the proto-oncogene ras and specific isoforms (particularly ?) of protein kinase C (PKC);and they can promote a rapid progression of human renal cancer through the over-expression of vascular endothelial growth factor (VEGF) and VEGF-induced angiogenesis. We have also identified the possible role of a novel molecule CARABIN (an endogenous inhibitor of both calcineurin and Ras) in CNI- induced ras activation, as CNI treatment was found to down-regulate CARABIN. In contrast, we recently observed that RAPA treatment could significantly inhibit CNI-induced and Ras-mediated over-expression of VEGF, and CNI-induced rapid progression of post-transplantation renal cancer. This suggests possible involvement of the mTOR pathway in CNI-induced tumor progression. Presently, it is a challenge for the clinicians to fix a safe but effective immunosuppressive therapy for the transplant patients to inhibit allograft rejection, as well as to prevent cancer development. Thus, new therapeutic targets need to be explored in order to prevent CNI-induced and mTOR-mediated cancers. Our studies suggest a novel cross-talk among CNI-induced signaling molecules and mTOR for the regulation of VEGF expression in renal cancer cells. However, the significance of CARABIN and PKC-? in regulating CNI-induced and mTOR-mediated VEGF over- expression and cancer progression is totally unexplored. Our hypothesis is that the down-regulation of CARABIN and activation of PKC-? plays a major role in CNI-induced and mTOR-mediated renal cancer progression through the over-expression of VEGF.
Our Specific Aims will examine: 1) functional significance of CARABIN, PKC-?, and mTOR in CNI-induced VEGF over-expression for the regulation of pathways in renal cancer progression;and 2) the role(s) of CARABIN and PKC-? in CNI-induced and mTOR-mediated renal cancer progression by using an in vivo tumor xenograft model. Together, these studies should explore the specific roles of CARABIN and PKC-? in promoting mTOR-induced and VEGF-mediated renal cancer progression following CNI therapy. We believe that these studies are ideal for the R21 mechanism, as they initiate the exploration for the role of novel molecules in CNI-induced cancers, and they have significant potential to result in high impact findings with clinical significance.
The development of cancer is a critical problem in patients treated with immunosuppressive agents. This research proposal will examine the specific roles of a novel molecule CARABIN, and PKC-??in calcineurin inhibitor (CNI)-induced and mTORmediated renal cancer. Our objective is to examine how the over-expression of CARABIN or the inhibition of PKC-??may prevent the rapid progression of CNI-induced and vascular endothelial growth factor (VEGF)-mediated renal cancer that involves mTOR.
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