RADIORESISTANCE INDUCED BY THE HIGH-MOLECULAR FORMS OF THE BASIC FIBROBLAST GROWTH-FACTOR IS ASSOCIATED WITH AN INCREASED G(2) DELAY AND A HYPERPHOSPHORYLATION OF P34(CDC2) IN HELA-CELLS

The basic fibroblast growth factor-(bFGF) mediated signal transduction pathway has been implicated in cellular resistance to ionizing radiat ion, bFGF is synthesized from the same mRNA in four isoforms resulting from alternative initiations of translation at three CUG start codons (24, 21.5, and 21 kDa) and one AUG start codon (18 kDa), We analyzed the implication of high- and low-molecular forms of bFGF in radioresis tance acquisition, For this, we transfected HeLa cells with retroviral vector containing either the CUG-initiated 24-kDa molecular form (HeL a 3A cells), the AUG-initiated 18-kDa molecular bFGF form (HeLa 5A cel ls), or the vector alone (HeLa PINA cells), A significantly increased radioresistance was obtained only in HeLa 3A cells (Dq = 810 +/- 24 cG y) compared with wild-type cells (Dq = 253 +/- 49 cGy) or HeLa PINA ce lls (Dq = 256 +/- 29 cGy; P < 0.001), This radioprotective effect was independent of an inhibition of radiation-induced apoptosis but relate d to an increased G(2) duration after irradiation and to an hyperphosp horylation of p34(cdc2) kinase, Knowledge of the high-molecular bFGF f orm-induced radioresistance pathway could offer novel targets for decr easing the radioresistance phenotype of tumors expressing high amounts of bFGF, such as glioblastoma.