title: Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes.
abstract: The influence of activated ras oncogenes on the sensitivity of human tumor cells to killing by radiation has been an unresolved question in radiobiology. We have examined this question by measuring the radiation sensitivity of human tumor cell lines with oncogenic mutations in their H- or K-ras genes after treatment with prenyltransferase inhibitors that prevent the posttranslational modification of ras required for its activity. Using two measures of clonogenic survival, we have demonstrated radiosensitization in cell lines with oncogenic H-ras mutations or with oncogenic K-ras mutations when ras processing was inhibited by prenyltransferase inhibitor treatment. In contrast, the inhibition of ras processing in cell lines expressing wild-type ras had no effect on radiation-induced cell death. The prenyltransferase inhibitors themselves inhibited clonogenic survival in some cases, but this inhibition did not correlate with ras mutational status. Although treatment with prenyltransferase inhibitors and radiation resulted in a greater reduction of clonogenicity than either treatment alone in cells with wild-type ras, treatment with both agents had a synergistic effect on cell killing in tumor cells with ras mutations. Our results demonstrate that the inhibition of oncogenic ras activity in human tumor cells can reduce the radiation survival of these cells, suggesting that oncogenic ras can contribute to radiation resistance in human tumors. These results further demonstrate the potential of using prenyltransferase inhibitors in combination with radiotherapy in the treatment of human malignancies.
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Bernhard
authors.forename: W G
authors.initials: WG
authors.lastname: McKenna
authors.forename: A D
authors.initials: AD
authors.lastname: Hamilton
authors.forename: S M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Y
authors.initials: Y
authors.lastname: Qian
authors.forename: J M
authors.initials: JM
authors.lastname: Wu
authors.forename: R J
authors.initials: RJ
authors.lastname: Muschel
mesh_terms: D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D009154:Mutation; D017368:Protein Prenylation / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism / Q000502:physiology*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; C096856:FTI 277; D011838:Radiation-Sensitizing Agents; D008715:Methionine; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)