Oncogenic K-Ras signals through epidermal growth factor receptor and wild-type H-Ras to promote radiation survival in pancreatic and colorectal carcinoma cells.
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 alpha 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.
Cengel
Keith A
KA
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA. cengel@xrt.upenn.edu
Voong
K Rahn
KR
Chandrasekaran
Sanjay
S
Maggiorella
Laurence
L
Brunner
Thomas B
TB
Stanbridge
Eric
E
Kao
Gary D
GD
McKenna
W Gillies
WG
Bernhard
Eric J
EJ
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D066246:ErbB Receptors / Q000502:physiology* / Q000528:radiation effects*; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D011905:Genes, ras / Q000502:physiology* / Q000528:radiation effects*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D015398:Signal Transduction / Q000235:genetics* / Q000528:radiation effects*
D066246:ErbB Receptors