Dehydroepiandrosterone inhibits the proliferation and induces the death of HPV-positive and HPV-negative cervical cancer cells through an androgen- and estrogen-receptor independent mechanism

• Published in: The FEBS journal Vol. 276; no. 19; pp. 5598 - 5609
• Main Authors: Girón, Roma A, Montaño, Luis F, Escobar, María L, López-Marure, Rebeca
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01-10-2009; Blackwell Publishing Ltd
• Subjects: androgen receptor; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biochemistry; Cell cycle; Cell Cycle - drug effects; Cell Death - drug effects; Cell Line, Tumor; cell proliferation; Cell Proliferation - drug effects; Cervical cancer; Dehydroepiandrosterone - pharmacology; DHEA; estrogen-receptor; Female; HeLa Cells; Hormones; HPV; Human papillomavirus; Human papillomavirus 16 - isolation & purification; Human papillomavirus 18 - isolation & purification; Humans; Necrosis; Receptors, Androgen - metabolism; Receptors, Estrogen - metabolism; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-4658.2009.07253.x

Dehydroepiandrosterone (DHEA) has a protective role against epithelial-derived carcinomas; however, the mechanisms remain unknown. We determined the effect of DHEA on cell proliferation, the cell cycle and cell death in three cell lines derived from human uterine cervical cancers infected or not with human papilloma virus (HPV). We also determined whether DHEA effects are mediated by estrogen and androgen receptors. Proliferation of C33A (HPV-negative), CASKI (HPV16-positive) and HeLa (HPV18-positive) cells was evaluated by violet crystal staining and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction. Flow cytometry was used to evaluate the phases of the cell cycle, and cell death was detected using a commercially available carboxyfluorescein apoptosis detection kit that determines caspase activation. DNA fragmentation was determined using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Flutamide and ICI 182,780 were used to inhibit androgen and estrogen receptors, respectively, and letrozol was used to inhibit the conversion of DHEA to estradiol. Our results show that DHEA inhibited cell proliferation in a dose-dependent manner in the three cell lines; the DHEA IC₅₀ doses were 50, 60 and 70 μ m for C33A, CASKI and HeLa cells, respectively. The antiproliferative effect was not abrogated by inhibitors of androgen and estrogen receptors or by an inhibitor of the conversion of testosterone to estradiol, and this effect was associated with an increase in necrotic cell death in HPV-negative cells and apoptosis in HPV-positive cells. These results suggest that DHEA strongly inhibits the proliferation of cervical cancer cells, but its effect is not mediated by androgen or estrogen receptor pathways. DHEA could therefore be used as an alternative in the treatment of cervical cancer.