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Radioresistance Induced by the High Molecular Forms of the Basic Fibroblast Growth Factor Is Associated with an Increased G₂ Delay and a Hyperphosphorylation of p34^CDC2 in HeLa Cells¹

Laboratoire d'Oncologie Cellulaire et Moléculaire, EA/UPRES 2048, Faculté des Sciences Pharmaceutiques, Université Paul Sabatier [E. C-J., C. T., S. M., B. C., G. F.] and Département de Radiothérapie, Centre de Lutte Contre le Cancer Claudius Regaud [E. C-J., N. D-S.], 20-24 rue du Pont St.-Pierre, 31052 Toulouse, France; Laboratoire d'Endocrinologie et Communication cellulaire, INSERM U 397, CHU Rangueil, Bat L3, Chemin du vallon, 31052 Toulouse, France [C. T., A. M., H. P., G. F.]; and Unité de Radiophysique, Centre Jean Perrin, 58 rue Montalembert, 63011 Clermont-Ferrand, Cedex, France [J-J. B.]

The basic fibroblast growth factor-(bFGF) mediated signal transduction pathway has been implicated in cellular resistance to ionizing radiation. 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 radioresistance acquisition. For this, we transfected HeLa cells with retroviral vector containing either the CUG-initiated 24-kDa molecular form (HeLa 3A cells), the AUG-initiated 18-kDa molecular bFGF form (HeLa 5A cells), or the vector alone (HeLa PINA cells). A significantly increased radioresistance was obtained only in HeLa 3A cells (Dq = 810 ± 24 cGy) compared with wild-type cells (Dq = 253 ± 49 cGy) or HeLa PINA cells (Dq = 256 ± 29 cGy; P < 0.001). This radioprotective effect was independent of an inhibition of radiation-induced apoptosis but related to an increased G₂ duration after irradiation and to an hyperphosphorylation of p34^cdc2 kinase. Knowledge of the high-molecular bFGF form-induced radioresistance pathway could offer novel targets for decreasing the radioresistance phenotype of tumors expressing high amounts of bFGF, such as glioblastoma.

¹ This work was supported by the Federation Nationale des Centres de Lutte Contre le Cancer (comité Midi-Pyrénées).

² To whom requests for reprints should be addressed.

Received 9/23/96. Accepted 2/ 2/97.

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