The Effects of betulinic acid on microRNA-27a regulated target genes in MDA-MB-231 breast cancer cells
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abstract
Betulinic acid (BA), a pentacyclic triterpene isolated from tree bark is cytotoxic to cancer cells and tumors by inhibiting their growth and inducing apoptosis. There is evidence that specificity proteins (Sps), such as Sp1, Sp3 and Sp4, are overexpressed in tumors and contribute to the proliferative and angiogenic phenotype associated with cancer cells. This objective of this study was to determine the efficacy of BA in decreasing Sps expression and underlying mechanisms. Our results show that BA decreased proliferation of estrogenreceptor negative breast cancer cell line MDAMB231 within a concentrationrange of 2.510 mMol/L. BA also decreased Sp1, Sp3, and Sp4 expression and this was accompanied by increased zinc finger ZBTB10 gene expression, a putative Sprepressor (ZBTB10) and decreased microRNA27a levels, a microRNA involved in the regulation of ZBTB10. Similar results were observed in MDAMB231 cells transfected with antisense miR27a and ZBTB10 expression plasmid. Both asmiR27a and ZBTB10 overexpression decreased the percentage of cells in S phase of the cell cycle; however, ZBTB10 increased the percentage of cells in G0/G1, whereas asmiR27a increased the percentage in G2/M. This latter response was associated with induction of Myt1 (a miR27a target gene) which causes inhibition in G2/M by phosphorylation of cdc2. The effects to BA can be reversed by transient transfection with a mimic of miR27a. These results show that part of the underlying mechanism of the anticancer effect of BA is based on a decreased miR27a, accompanied by increased expression of Myt1 and ZBTB10 resulting in ZBTB10dependent suppression of Sp proteins and dependent genes.
