The Ras radiation resistance pathway.

The critical pathways determining the resistance of tumor cells to ionizing radiation are poorly defined. Because the ras oncogene, a gene activated in many human cancers treated with radiotherapy, can induce increased radioresistance, we have asked which Ras effector pathways are significant in conferring a survival advantage to tumor cells. The phosphoinositide-3-kinase (PI3K) inhibitor LY294002 radiosensitized cells bearing mutant ras oncogenes, but the survival of cells with wild-type ras was not affected. Inhibition of the PI3K downstream target p70S6K by rapamycin, the Raf-MEK-MAPK pathway with PD98059, or the Ras-MEK kinase-p38 pathway with SB203580 had no effect on radiation survival in cells with oncogenic ras. Expression of active PI3K in cells with wild-type ras resulted in increased radiation resistance that could be inhibited by LY294002. These experiments have indicated the importance of PI3K in mediating enhanced radioresistance and have implicated PI3K as a potential target for specific radiosensitization of tumors.

[1]  R. Muschel,et al.  Direct evidence for the contribution of activated N-ras and K-ras oncogenes to increased intrinsic radiation resistance in human tumor cell lines. , 2000, Cancer research.

[2]  K. Rosenzweig,et al.  Radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  S. A. Roberts,et al.  Intrinsic radiosensitivity and prediction of patient response to radiotherapy for carcinoma of the cervix. , 1993, British Journal of Cancer.

[4]  P. Cohen,et al.  Specificity and mechanism of action of some commonly used protein kinase inhibitors. , 2000, The Biochemical journal.

[5]  E. Chang,et al.  3'-End conjugates of minimally phosphorothioate-protected oligonucleotides with 1-O-hexadecylglycerol: synthesis and anti-ras activity in radiation-resistant cells. , 2000, Bioconjugate chemistry.

[6]  P. Kolm,et al.  Epidermal growth factor receptor: an independent predictor of survival in astrocytic tumors given definitive irradiation. , 1996, International journal of radiation oncology, biology, physics.

[7]  C. Sherr.  The Pezcoller lecture: cancer cell cycles revisited. , 2000, Cancer research.

[8]  F. McCormick,et al.  Opposing Effects of Ras on p53 Transcriptional Activation of mdm2 and Induction of p19ARF , 2000, Cell.

[9]  Michael J. Fry,et al.  Phosphatidylinositol-3-OH kinase direct target of Ras , 1994, Nature.

[10]  C. Marshall,et al.  PI-3-kinase is an essential anti-apoptotic effector in the proliferative response of primary human epithelial cells to mutant RAS , 2000, Oncogene.

[11]  R. Muschel,et al.  RAS-Mediated Radiation Resistance is not Linked to MAP Kinase Activation in Two Bladder Carcinoma Cell Lines , 2000, Radiation research.

[12]  C. Belka,et al.  MEK1 and Erk1/2 kinases as targets for the modulation of radiation responses. , 2000, Anticancer research.

[13]  R. Muschel,et al.  The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts. , 1996, Cancer research.

[14]  M. Birnbaum,et al.  Akt/Protein Kinase B Isoforms Are Differentially Regulated by Epidermal Growth Factor Stimulation* , 2000, The Journal of Biological Chemistry.

[15]  A. Bagg,et al.  Antisense raf oligodeoxyribonucleotide is a radiosensitizer in vivo. , 1999, Antisense & nucleic acid drug development.

[16]  E. Elion.  Routing MAP Kinase Cascades , 1998, Science.

[17]  C. Ling,et al.  The role of the H-ras oncogene in radiation resistance and metastasis. , 1990, International journal of radiation oncology, biology, physics.

[18]  T. Whiteside,et al.  Activation of Raf by ionizing radiation , 1996, Nature.

[19]  M. Herlyn,et al.  Contribution of phosphatidylinositol 3‐kinase to radiation resistance in human melanoma cells , 1999, Molecular carcinogenesis.

[20]  B. Fertil,et al.  Predictive value of in vitro radiosensitivity parameters in head and neck cancers and cervical carcinomas: preliminary correlations with local control and overall survival. , 1993, International journal of radiation oncology, biology, physics.

[21]  L. Schriml,et al.  Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. , 1999, Journal of the National Cancer Institute.

[22]  C. Der,et al.  The Ras branch of small GTPases: Ras family members don't fall far from the tree. , 2000, Current opinion in cell biology.

[23]  W. Fantl,et al.  Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase. , 1995, Science.

[24]  D. Samid,et al.  Increased radioresistance of ejras‐transformed human osteosarcoma cells and its modulation by lovastatin, an inhibitor of p21ras isoprenylation , 1993, International journal of cancer.

[25]  M. Weller,et al.  PTEN gene transfer in human malignant glioma: sensitization to irradiation and CD95L-induced apoptosis , 1999, Oncogene.

[26]  R. Muschel,et al.  Farnesyltransferase Inhibitors Potentiate the Antitumor Effect of Radiation on a Human Tumor Xenograft Expressing Activated HRAS1 , 2000, Radiation research.

[27]  C. Ling,et al.  Radioresistance induced by oncogenic transformation. , 1989, Radiation research.

[28]  A. Pfeifer,et al.  Effects of c-raf-1 and c-myc expression on radiation response in an in vitro model of human small-cell-lung carcinoma. , 1998, Biochemical and biophysical research communications.

[29]  G. Paludetti,et al.  Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma. , 1996, British Journal of Cancer.

[30]  P. Dent,et al.  Ionizing Radiation-Induced Mitogen-Activated Protein (MAP) Kinase Activation in DU145 Prostate Carcinoma Cells: MAP Kinase Inhibition Enhances Radiation-Induced Cell Killing and G2/M-Phase Arrest , 2000 .

[31]  R. Weichselbaum,et al.  Effect of antisense c-raf-1 on tumorigenicity and radiation sensitivity of a human squamous carcinoma. , 1989, Science.

[32]  R. Muschel,et al.  Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes. , 1998, Cancer research.