Inhibition of oncogene-induced inflammatory chemokines using a farnesyltransferase inhibitor.

Authors

Katharine C Degeorge, Department of Immunology and Microbiology/Otolaryngology-Head and Neck Surgery, Kimmel Cancer Institute, Thomas Jefferson UniversityFollow
Brent R Degeorge, Center for Translational Medicine, Department of Medicine, Thomas Jefferson UniversityFollow
James S Testa, Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson UniversityFollow
Jay L Rothstein, Department of Immunology and Microbiology/Otolaryngology-Head and Neck Surgery, Kimmel Cancer Institute, Thomas Jefferson University; Amgen, Inc.Follow

Document Type

Article

Publication Date

2-27-2008

Comments

This article has been peer reviewed. It was published in: Journal of Inflammation.

Volume 5, 2008, Article number 3.

The published version is available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268934/. DOI: 10.1186/1476-9255-5-3

Copyright © 2008 DeGeorge et al; licensee BioMed Central Ltd.

Abstract

BACKGROUND: Farnesyltransferase inhibitors (FTI) are small molecule agents originally formulated to inhibit the oncogenic functions of Ras. Although subsequent analysis of FTI activity revealed wider effects on other pathways, the drug has been demonstrated to reduce Ras signaling by direct measurements. The purpose of the current study was to determine if FTI could be used to inhibit the inflammatory activities of a known Ras-activating human oncoprotein, RET/PTC3. RET/PTC3 is a fusion oncoprotein expressed in the thyroid epithelium of patients afflicted with thyroid autoimmune disease and/or differentiated thyroid carcinoma. Previous studies have demonstrated that RET/PTC3 signals through Ras and can provoke nuclear translocation of NFkappaB and the downstream release of pro-inflammatory mediators from thyroid follicular cells in vitro and in vivo, making it an ideal target for studies using FTI.

METHODS: For the studies described here, an in vitro assay was developed to measure FTI inhibition of RET/PTC3 pro-inflammatory effects. Rat thyrocytes transfected with RET/PTC3 or vector control cDNA were co-cultured with FTI and examined for inhibition of chemokine expression and secretion measured by RT-PCR and ELISA. Immunoblot analysis was used to confirm the level at which FTI acts on RET/PTC3-expressing cells, and Annexin V/PI staining of cells was used to assess cell death in RET/PTC3-expressing cells co-cultured with FTI.

RESULTS: These analyses revealed significant mRNA and protein inhibition of chemokines Ccl2 and Cxcl1 with nanomolar doses of FTI. Neither RET/PTC3 protein expression nor apoptosis were affected at any dose of FTI investigated.

CONCLUSION: These data suggest that FTI may be applied as an effective inhibitor for RET/PTC3-oncogene induced pro-inflammatory mediators.

Recommended Citation

Degeorge, Katharine C; Degeorge, Brent R; Testa, James S; and Rothstein, Jay L, "Inhibition of oncogene-induced inflammatory chemokines using a farnesyltransferase inhibitor." (2008). Kimmel Cancer Center Faculty Papers. Paper 39.
https://jdc.jefferson.edu/kimmelccfp/39

PubMed ID

18304343