Human papillomavirus (HPV)
infection is believed to be the central cause of
cervical cancer. The
viral proteins E6 and E7 from high-risk HPV types prevent cells from differentiating apoptosis and inducing hyperproliferative lesions. Human cervical
carcinoma HeLa cells contain integrated human papillomavirus type 18 (HPV-18).
Retinoic acid (RA) is a key regulator of epithelial cell differentiation and a
growth inhibitor in vitro of HeLa cervical
carcinoma cells. Cellular responses to RA are mediated by nuclear
retinoic acid receptors (RARs) and
retinoid X receptors. On the other hand,
histone deacetylase inhibitors have been shown to be chemopreventive agents for the treatment of
cancer cells. In this article, we have examined the antiproliferative effect of RA and
histone deacetylase inhibitor BML-210 on HeLa cells, and particularly the effects on
protein expression that may be involved in the cell cycle control and apoptosis. Our data suggest that a combination of RA and
BML-210 leads to cell growth inhibition with subsequent apoptosis in a treatment time-dependent manner. We confirm that
BML-210 alone or in combination with RA causes a marked increase in the level of p21. The changes in the p53 level are under the influence of p38 phosphorylation. We also discovered that the
histone deacetylase inhibitor BML-210 causes increased levels of
anti-apoptotic protein Bcl-2 and phosphorylated
p38 MAP Kinase; the latter link in cell cycle arrest with response to extracellular stimuli. Our results suggest that RA and
BML-210 are involved in different signaling pathways that regulate cell cycle arrest and lead to apoptosis of HeLa cells.