Direct evidence for the contribution of activated N-ras and K-ras oncogenes to increased intrinsic radiation resistance in human tumor cell lines.
Transformation with ras oncogenes results in increased radiation sur vival in many but not all cells. In addition, prenyltransferase inhibitors which inhibit ras proteins by blocking posttranslational modification radiosensitize cells with oncogenic ras. These findings suggest that oncogenic ras contributes to intrinsic radiation resistance. However, because introduction of ras oncogenes does not increase radiation survival in all cells and because prenyltransferase inhibitors target molecules other than ras, these studies left the conclusion that ras increases the intrinsic radi ation resistance of tumor cells in doubt. Here we show that genetic inactivation of K- or N-ras oncogenes in human tumor cells (DLD-1 and HT1080, respectively) leads to increased radiosensitivity. Reintroduction of the activated N-ras gene into the HT1080 line, having lost its mutant allele, resulted in increased radiation resistance. This study lends further support to the hypothesis that expression of activated ras can contribute to intrinsic radiation resistance in human tumor cells and extends this finding to the K- and N- members of the ras family. These findings support the development of strategies that target ras for inactivation in the treatment of cancer.
Bernhard
E J
EJ
Department of Radiation Oncology, University of Pennsylvania, Philadelphia 19104-6072, USA. bernhard@mail.med.upenn.edu
Stanbridge
E J
EJ
Gupta
S
S
Gupta
A K
AK
Soto
D
D
Bakanauskas
V J
VJ
Cerniglia
G J
GJ
Muschel
R J
RJ
McKenna
W G
WG
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D000483:Alleles; D017209:Apoptosis / Q000528:radiation effects; D002455:Cell Division / Q000235:genetics; D002470:Cell Survival / Q000528:radiation effects; D002999:Clone Cells; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D005354:Fibrosarcoma / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D011836:Radiation Tolerance / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000502:physiology / Q000528:radiation effects*