Abstract
Abstract The development of cancer is an increasing and major problem in immunosuppressed patients, particularly after solid organ transplantation. In part, the increased cancer risk is associated with the use of immunosuppressive agents, especially calcineurin inhibitors (CNIs). The CNIs are used to prevent inflammatory diseases and allograft rejection. However, little is known about the mechanism(s) underlying their ability to promote the development and recurrence of cancer. We have recently demonstrated that CNI can mediate the transcriptional activation of the angiogenic cytokine vascular endothelial growth factor (VEGF) and promote a rapid progression of human renal cancer. In contrast, the mTOR inhibitor rapamycin (RAPA), which is thought to have anti-cancer effects, has been reported to decrease VEGF expression. Here, we investigated whether the CNI cyclosporine (CsA) and RAPA could alter the mRNA stability of VEGF in 786-0 and Caki-1 renal cancer cells. By using actinomycin-D, we observed that CsA increased, while RAPA decreased the VEGF mRNA stability as observed by real time PCR. It is established that the mRNA-binding protein HuR may play a critical role in VEGF mRNA stability. By using HuR-siRNA, we found that the knockdown of HuR significantly decreased the CNI-induced VEGF mRNA stability. By Western blot analysis, it has been observed that CNI treatment induced the translocation of HuR from the nucleus to the cytoplasm; CNI also induced the association between HuR and protein kinase C (PKC)-δ, and promoted the phosphorylation of HuR. Interestingly, there was no significant change in the cytoplasmic translocation of HuR following RAPA treatment. Finally, we found that the inhibition of PKC-δ using a dominant-negative plasmid significantly decreased the CsA-induced cytoplasmic translocation of HuR and the VEGF mRNA stability. Together, we suggest that targeting the pathways that promote the transcription as well as the mRNA stability (post-transcriptional modification) of VEGF in response to CNI might serve as novel therapeutics for the prevention and treatment of cancer in immunosuppressed patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-371.
Published Version
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