Calcineurin inhibitors activate the proto-oncogene Ras and promote protumorigenic signals in renal cancer cells.
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.
Datta
Dipak
D
Division of Nephrology and Transplantation Research Center, Children's Hospital Boston and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Contreras
Alan G
AG
Basu
Aninda
A
Dormond
Olivier
O
Flynn
Evelyn
E
Briscoe
David M
DM
Pal
Soumitro
S
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D015536:Down-Regulation; D020690:GTPase-Activating Proteins; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction; D016559:Tacrolimus / Q000494:pharmacology; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D065095:Calcineurin Inhibitors; D020690:GTPase-Activating Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C517115:TBC1D10C protein, human; D016572:Cyclosporine; D048490:raf Kinases; D019703:Calcineurin; D018631:ras Proteins; D016559:Tacrolimus