Calcineurin inhibitors activate the proto-oncogene Ras and promote protumorigenic signals in renal cancer cells.

Details

Serval ID
serval:BIB_96242209D3BA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Calcineurin inhibitors activate the proto-oncogene Ras and promote protumorigenic signals in renal cancer cells.
Journal
Cancer Research
Author(s)
Datta D., Contreras A.G., Basu A., Dormond O., Flynn E., Briscoe D.M., Pal S.
ISSN
1538-7445[electronic]
Publication state
Published
Issued date
2009
Peer-reviewed
Oui
Volume
69
Number
23
Pages
8902-9
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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 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.
Keywords
Adaptor Proteins, Signal Transducing/biosynthesis, Animals, Calcineurin/antagonists & inhibitors, Calcineurin/metabolism, Cell Growth Processes/physiology, Cell Line, Tumor, Cyclosporine/pharmacology, Down-Regulation, Humans, Kidney Neoplasms/enzymology, Kidney Neoplasms/metabolism, Mice, Mice, Nude, Mice, SCID, Signal Transduction, Tacrolimus/pharmacology, raf Kinases/metabolism, ras Proteins/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
09/02/2010 11:12
Last modification date
20/08/2019 14:58
Usage data