The mechanism of retinoic acid radiosensitization is independent of AP-1 repression in a cervical carcinoma cell line.
BACKGROUND
Retinoic acid (RA) has been shown to radiosensitize some tumor cell lines. RA regulates gene expression through nuclear receptors that bind to retinoic acid response elements in gene promoters and that inhibit activator protein-1 (AP-1) transcription factor activity.


OBJECTIVE
The aim of this study was to determine if the mechanism of radiosensitization of the CC-1 human cervical carcinoma cell line by 9-cis-RA (9cRA) involves repression of AP-1 activity.


METHODS
The CCA reporter cell line was established from CC-1 by permanent transfection with the ColCAT reporter plasmid which consists of the chloramphenicol acetyltransferase (CAT) gene under the control of the AP-1-responsive collagenase gene promoter. CCA cultures were treated with various combinations of 9cRA, 60Co radiation, and an AP-1 inducer called O-tetradecanoylphorbol 13-acetate (TPA). Cultures were then evaluated in parallel for CAT expression as a measure of AP-1 activity and for clonogenic survival as a measure of radiosensitization.


RESULTS
The CCA reporter line exhibited a radiation dose-responsive induction of AP-1 activity that was decreased by 5 microM 9cRA and increased by 50 ng/ml TPA. Simultaneous treatment with TPA and 9cRA prevented 9cRA repression of AP-1 and resulted in AP-1 activity above basal level. The 9cRA radiosensitized CC-1 cultures with a dose modification factor of 1.5. The survival of cultures treated simultaneously with TPA and 9cRA was statistically identical to that of cultures treated with 9cRA alone.


CONCLUSIONS
Although TPA prevented AP-1 repression by 9cRA, it did not prevent radiosensitization in CCA cultures, therefore the mechanism of radiosensitization of CCA by 9cRA is independent of AP-1 repression.
D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects*; D006801:Humans; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000187:drug effects* / Q000528:radiation effects*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics*