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

被引:77
作者
Cengel, Keith A.
Voong, K. Rahn
Chandrasekaran, Sanjay
Maggiorella, Laurence
Brunner, Thomas B.
Stanbridge, Eric
Kao, Gary D.
McKenna, W. Gillies
Bernhard, Eric J.
机构
[1] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA
[2] Ctr Antoine Lacassagne, Inst Signal Transduct Dev Biol & Canc, F-06054 Nice, France
[3] Univ Erlangen Nurnberg, Dept Radiat Oncol, Erlangen, Germany
[4] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA
[5] Univ Oxford, Dept Radiat Oncol & Biol, Oxford OX1 2JD, England
来源
NEOPLASIA | 2007年 / 9卷 / 04期
基金
英国医学研究理事会;
关键词
Ras; EGFR; radiosensitivity; signal transduction; cancer;
D O I
10.1593/neo.06823
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:341 / 348
页数:8
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