ABSTRACT
Ursolic acid (UA), a naturally occurring pentacyclic triterpene, is a potent in vitro anticancer agent, acting through control of growth, apoptosis, and differentiation. As the anticancer effect and the mechanism of action of ursolic acid on human breast cancer cells has not been extensively studied, we performed an evaluation of the effects of UA on apoptosis in MCF-7 cells. UA was found to inhibit the proliferation of MCF-7 cells in a concentration and time-dependent manner. After treatment, UA-induced apoptosis was accompanied by a significant decrease in CyclinD1/CDK4 expression, which can be regulated by FoxM1. Previous studies demonstrated that FoxM1 orchestrates the transcription of genes that are essential for cell cycle progression and cell proliferation. The result of Western blot suggested that ursolic acid inhibited the expression of FoxM1. Taken together, the data suggest that the proapoptotic effect of UA on MCF-7 cells is mediated by inhibition of FoxM1 and is highly correlated with inactivation of CyclinD1/CDK4.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Breast Neoplasms/metabolism , Forkhead Transcription Factors/biosynthesis , Triterpenes/pharmacology , Blotting, Western , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin D1/metabolism , Cyclin-Dependent Kinase 4/metabolism , Female , Forkhead Box Protein M1 , Gene Expression/drug effects , Humans , Reverse Transcriptase Polymerase Chain Reaction , Ursolic AcidABSTRACT
SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase that plays an important role in transcriptional regulation in human carcinogenesis. It can specifically methylate histone H3 at lysine 4 and activate the transcription of a set of downstream genes, including several oncogenes (e.g., N-myc, CrkL, Wnt10b, RIZ and hTERT) and genes involved in the control of cell cycle (e.g., CyclinG1 and CDK2) and signal transduction (e.g., STAT1, MAP3K11 and PIK3CB). To determine the effects of SMYD3 over-expression on cell proliferation, we transfected SMYD3 into MDA-MB-231 cells and found that these cells showed several transformed phenotypes as demonstrated by colony growth in soft agar. Besides, we show here that down-regulation of SMYD3 could induce G1-phase cell cycle arrest, indicating the potent induction of apoptosis by SMYD3 knockdown. These results suggest the regulatory mechanisms of SMYD3 on the acceleration of cell cycle and facilitate the development of strategies that may inhibit the progression of cell cycle in breast cancer cells.
