All-trans-retinoic acid inhibits the proliferation of cell lines derived from human cervical neoplasia

Abstract

The purpose of this study was to determine whether all-trans-retinoic acid (RA) can inhibit the growth of cervical neoplastic cells by inducing differentiation or by increasing the secretion of transforming growth factor- β (TGF-β). Normal and HPV DNA-positive cervical cells (2 cell lines derived from cervical intraepithelial neoplasia (CIN), 2 HPV DNA-transfected cell lines, and 6 cervical carcinoma cell lines) were treated with RA (1 to 1000 nM), and both total viable cell count and [3H]thymidine incorporation were used to evaluate proliferation. In vitro differentiation was evaluated in organotypic (collagen gel raft) cultures with hematoxylin/eosin staining, and using specific immunostaining for fillagrin and cytokeratin 10. TGF-β1 and TGF-β2 secretion were measured with specific SELISAs. One-way analysis of variance and t tests were performed. RA causes a dose-dependent (P < 0.05) growth arrest of comparable magnitude in normal ectocervical cells, in HPV DNA-transfected cell lines, in CIN-derived cell lines, and in four of six carcinoma cell lines. Endocervical cells and two carcinoma cell lines are unaffected. In vitro differentiation is decreased in CIN cells and is unchanged in carcinomas treated with RA as compared to control. Secretion of either TGF-β1 or TGF-β2 is significantly increased (P < 0.05) in response to RA, both in RA-sensitive and in RA-resistant cells. RA induces growth inhibition in cervical neoplastic cell lines, including cervical carcinoma cells. This does not appear to be the result of increased differentiation or of increased TGF-β secretion.