Calcineurin Inhibitors Activate the Proto-Oncogene Ras and Promote Protumorigenic Signals in Renal Cancer Cells

Abstract

The development of cancer is a major problem in immunosuppressed patients, particularly after solid organ transplantation. We have recently shown that calcineurin inhibitors (CNI) used to treat transplant patients may play a critical role in the rapid progression of renal cancer. To examine the intracellular signaling events for CNI-mediated direct tumorigenic pathway(s), we studied the effect of CNI on the activation of proto-oncogenic Ras in human normal renal epithelial cells (REC) and renal cancer cells (786-0 and Caki-1). We found that CNI treatment significantly increased the level of activated GTP-bound form of Ras in these cells. In addition, CNI induced the association of Ras with one of its effector molecules, Raf, but not with Rho and phosphatidylinositol 3-kinase; CNI treatment also promoted the phosphorylation of the Raf kinase inhibitory protein and the downregulation of carabin, all of which may lead to the activation of the RasRaf pathway. Blockade of this pathway through either pharmacologic inhibitors or gene-specific small interfering RNA significantly inhibited CNI-mediated augmented proliferation of renal cancer cells. Finally, it was observed that CNI treatment increased the growth of human renal tumors in vivo, and the Ras-Raf pathway is significantly activated in the tumor tissues of CNI-treated mice. Together, targeting the Ras-Raf pathway may prevent the development/progression of renal cancer in CNI-treated patients. [Cancer Res 2009;69(23):8902-9]

The Heme Oxygenase-1 Protein Is Overexpressed in Human Renal Cancer Cells following Activation of the Ras-Raf-ERK Pathway and Mediates Anti-Apoptotic Signal

“…However, the regulatory mechanism(s) of HO-1 overexpression in cancer cells, including renal cancer, is not well defined. Previously, we have shown that the proto-oncogene H-Ras is activated in human renal cancer cells following immunosuppressive therapy, and the activated H-Ras can mediate proliferation of tumor cells (37). In this study, for the first time, we demonstrate that activated H-Ras can promote HO-1 transcriptional activation and protein overexpression in renal cancer cells.…”

“…We have recently demonstrated that H-Ras becomes activated in human renal cancer cells under stress following treatment with immunosuppressive agents, and the activated H-Ras induces tumorigenic pathways (37). We have also observed that the expression of HO-1 is significantly up-regulated in renal cancer tissues, and the overexpressed HO-1 can inhibit tumor cell apoptosis (38).…”

Optimization of immunosuppressive medication upon liver transplantation against HCC recurrence

“…switch on oncogenes to promote cancer cell proliferation, survival and metastasis (41,42). A number of retrospective studies have demonstrated a dose related association between CNI IS and HCC recurrence after liver transplant (16,27,43).…”

Is murine gammaherpesvirus-68 (MHV-68) a suitable immunotoxicological model for examining immunomodulatory drug-associated viral recrudescence?

“…EBV-infected lymphocytes) to initiate re-activation of latent infection (Ryffel et al, 1992). Other reports have described the role of calcineurin inhibitors in activation of proto-oncogenic RAS (Datta et al, 2009). Indeed, these compounds may also be useful in the MHV-68 model and have already been tested with cyclosporine A (CsA).…”