RhoB controls the 24 kDa FGF-2-induced radioresistance in HeLa cells by preventing post-mitotic cell death.
Farnesylated Ras oncoprotein induces a cellular resistance to ionizing radiation that can be reversed by farnesyltransferase inhibitors (FTI). We previously demonstrated that, expression of the 24 kDa FGF2 isoform in wild type ras bearing HeLa cells, induced radioresistance which was also reversed by FTI. We tested the hypothesis that wild type Ras or RhoB, which has been proposed as a potential FTI target, could control the FGF-2-induced radioresistance mechanisms. For this, we expressed inducible dominant negative forms of Ras (RasN17) and Rho (RhoBN19) in 24 kDa FGF2 transfected HeLa cells and analysed their survival after irradiation. While no cell survival modification was observed after RasN17 induction, the expression of RhoBN19 induced a radiosensitization of FGF2 radioresistant HeLa cells in the same range as the one observed after a 48 h treatment with the specific FTI, R115777. Moreover, we showed that activated RhoB but not RhoA induced radioresistance in NIH3T3 cells. The radiosensitizer effect of RhoBN19 expression was due to the induction of the radiation induced post-mitotic cell death. Taken together, these data demonstrate that 24 kDa FGF-2-induced radioresistance is controlled by Rho pathways and suggest that RhoB should be a major determinant in cellular resistance to ionizing radiation.
Oncologie Cellulaire et Moléculaire, INSERM U563, Département d'Innovation thérapeutique et Oncologie Moléculaire, Centre de Lutte Contre le Cancer Claudius Regaud, 20-24 rue du Pont St Pierre, 31052 Toulouse Cedex, France.
Isabelle
I
Ader
Christine
C
Toulas
Florence
F
Dalenc
Caroline
C
Delmas
Jacques
J
Bonnet
Elizabeth
E
Cohen-Jonathan
Gilles
G
Favre
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D003435:Crotalid Venoms / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005799:Genes, Dominant; D006023:Glycoproteins / Q000494:pharmacology; D006367:HeLa Cells / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008938:Mitosis / Q000502:physiology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D030162:Reptilian Proteins; D018631:ras Proteins / Q000502:physiology; D020743:rhoB GTP-Binding Protein / Q000502:physiology*
D003435:Crotalid Venoms; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; C096856:FTI 277; D006023:Glycoproteins; D020033:Protein Isoforms; D011838:Radiation-Sensitizing Agents; D030162:Reptilian Proteins; C087438:phospholipase A2 inhibitor protein, Crotalus; D016222:Fibroblast Growth Factor 2; D008715:Methionine; D011065:Poly(ADP-ribose) Polymerases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D010741:Phospholipases A; D018631:ras Proteins; D020743:rhoB GTP-Binding Protein