Effects of Methylation Inhibition on Cell Prolieration and Metastasis of Human Breast Cancer Cells

Abstract

Breast cancer is the second most fatal cancer in women. Adenosine has been shown to induce apoptosis through various mechanisms including adenosine receptor activation, adenosine monophosphate (AMP) conversion, AMP-activated protein kinase activation, or conversion to S-adenosylhomocysteine, which is an inhibitor of S-adenosylmethionine-dependent methyltransferases. Since the pathways involved in the anticancer activity of adenosine analogues are not still clearly understood, I examined the relationship between methyltransferase inhibition and the anticancer, antimetastatic effect of adenosine dialdehyde (AdOx) which is known for AdoHcy hydrolase inhibitor, which result in methylation inhibition, using non-invasive and invasive human breast cancer cells (HBCs MCF-7 and MDA-MB 231, respectively). Morphological changes and condensed chromatin were observed in HBCs treated with AdOx. Cytotoxicity was increased and DNA synthesis and cell counts were decreased by AdOx in HBCs, but the cytotoxicity was higher in MCF-7 than in MDA-MB 231. In MDA-MB 231, AdOx lowered the expression of G1/S regulators and the tumor suppressor p21WAF1/Cip1. In MCF-7, apoptotic molecules and tumor suppressor p21WAF1/Cip1 expression were induced by AdOx. Colony dispersion and cell migration was inhibited by AdOx and the activities of matrix metalloproteinase-2 /-9, which are key enzymes for cancer invasion and migration, were decreased by AdOx. But, the mRNA levels of MMP-2 and MMP-9 were not affected in accordance with the changes in enzymatic activity. Mammary-specific serine protease inhibitor was increased by AdOx in both cell lines. These results suggest that methyltransferase inhibition by AdOx may decrease cell viability and influence cell cycle distribution and migratory potential, providing evidence of methylation inhibition as a potential target for anticancer and antimetastatic effects in HBCs.