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

Division of Nephrology and Transplantation Research Center, Children's Hospital Boston and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Soumitro Pal, Division of Nephrology, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. Phone: 617-919-2989; Fax: 617-730-0130; E-mail: soumitro.pal{at}childrens.harvard.edu.

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 Ras-Raf 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):OF1–8]

Key Words: Calcineurin inhibitor • Cancer • Ras • Raf