Oncogenic K-Ras signals through epidermal growth factor receptor and wild-type H-Ras to promote radiation survival in pancreatic and colorectal carcinoma cells

Keith A. Cengel, K. Rahn Voong, Sanjay Chandrasekaran, Laurence Maggiorella, Thomas B. Brunner, Eric Stanbridge, Gary D. Kao, W. Gillies McKenna, Eric J. Bernhard

Research output: Contribution to journalArticle

Abstract

Pancreatic and colorectal carcinomas frequently express oncogenic/mutant K-Ras that contributes to both tumorigenesis and clinically observed resistance to radiation treatment. We have previously shown that farnesyltransferase inhibitors (FTI) radiosensitize many pancreatic and colorectal cancer cell lines that express oncogenic K-ras at doses that inhibit the prenylation and activation of H-Ras but not K-Ras. In the present study, we have examined the mechanism of FTI-mediated radiosensitization in cell lines that express oncogenic K-Ras and found that wild-type H-Ras is a contributor to radiation survival in tumor cells that express oncogenic K-Ras. In these experiments, inhibiting the expression of oncogenic K-Ras, wild-type H-Ras, or epidermal growth factor receptor (EGFR) led to similar levels of radiosensitization as treatment with the FTI tipifarnib. Treatment with the EGFR inhibitor gefitinib led to similar levels of radiosensitization, and the combinations of tipifarnib or gefitinib plus inhibition of K-Ras, H-Ras, or EGFR expression did not provide additional radiosensitization compared with tipifarnib or gefitinib alone. Finally, supplementing culture medium with the EGFR ligand transforming growth factor A was able to reverse the radiosensitizing effect of inhibiting K-ras expression. Taken together, these findings suggest that EGFR-activated H-Ras signaling is initiated by oncogenic K-Ras to promote radiation survival in pancreatic and colorectal cancers.

Original languageEnglish (US)
Pages (from-to)341-348
Number of pages8
JournalNeoplasia
Volume9
Issue number4
DOIs
StatePublished - Apr 2007

Keywords

  • Cancer
  • EGFR
  • Radiosensitivity
  • Ras
  • Signal transduction

ASJC Scopus subject areas

  • Cancer Research

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  • Cite this

    Cengel, K. A., Voong, K. R., Chandrasekaran, S., Maggiorella, L., Brunner, T. B., Stanbridge, E., Kao, G. D., McKenna, W. G., & Bernhard, E. J. (2007). Oncogenic K-Ras signals through epidermal growth factor receptor and wild-type H-Ras to promote radiation survival in pancreatic and colorectal carcinoma cells. Neoplasia, 9(4), 341-348. https://doi.org/10.1593/neo.06823