Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells

Abstract

Soybean isoflavones have been used as a potential preventive agent in anticancer research for many years. Genistein is one of the most active flavonoids in soybeans. Accumulating evidence suggests that genistein alters a variety of biological processes in estrogen-related malignancies, such as breast and prostate cancers. However, the molecular mechanism of genistein in the prevention of human colon cancer remains unclear. Here we attempted to elucidate the anticarcinogenic mechanism of genistein in human colon cancer cells. First we evaluated the growth inhibitory effect of genistein and two other isoflavones, daidzein and biochanin A, on HCT-116 and SW-480 human colon cancer cells. In addition, flow cytometry was performed to observe the morphological changes in HCT-116/SW-480 cells undergoing apoptosis or cell cycle arrest, which had been visualized using Annexin V-FITC and/or propidium iodide staining. Real-time PCR and western blot analyses were also employed to study the changes in expression of several important genes associated with cell cycle regulation. Our data showed that genistein, daidzein and biochanin A exhibited growth inhibitory effects on HCT-116/SW-480 colon cancer cells and promoted apoptosis. Genistein showed a significantly greater effect than the other two compounds, in a time- and dose-dependent manner. In addition, genistein caused cell cycle arrest in the G2/M phase, which was accompanied by activation of ATM/p53, p21waf1/cip1 and GADD45α as well as downregulation of cdc2 and cdc25A demonstrated by q-PCR and immunoblotting assay. Interestingly, genistein induced G2/M cell cycle arrest in a p53-dependent manner. These findings exemplify that isoflavones, especially genistein, could promote colon cancer cell growth inhibition and facilitate apoptosis and cell cycle arrest in the G2/M phase. The ATM/p53-p21 cross-regulatory network may play a crucial role in mediating the anticarcinogenic activities of genistein in colon cancer.

Sodium Fluoride Arrests Renal G2/M Phase Cell-Cycle Progression by Activating ATM-Chk2-P53/Cdc25C Signaling Pathway in Mice

“…Guo et al [48] have shown that dietary NiCl 2 can cause G2/M phase cell-cycle arrest in kidneys of broiler via ATM-Chk1/Chk2 pathways. Zhang et al [49] have reported that genistein can induce G2/M cell-cycle arrest via the ATM/p53-dependent pathway in human colon cancer cells. It has been found also that mangiferin can induce cell-cycle arrest at the G2/M phase through the ATR-Chk1 pathway in HL-60 leukemia cells [50].…”

Diallyl disulfide induces G2/M arrest and promotes apoptosis through the p53/p21 and MEK-ERK pathways in human esophageal squamous cell carcinoma

“…In addition, cdc2 activation depends on the dephosphorylation of Tyr15 by cdc25c. Otherwise, p53 and the p53-responsive gene, p21, can suppress cyclin B1 and cdc2 expression by inhibiting either cdc2 kinase activity or blocking the interaction of cyclin B1-cdc2 complexes with their substrates, leading to G2/M-phase cell cycle arrest (23)(24)(25)(26)(27). Furthermore, the MEK-ERK pathway has crosstalk with p53/p21, and Bax is a key target of the p53 transcription process in aspects of cell apoptosis (26).…”

Expression of prostate stem cell antigen is downregulated during flavonoid-induced cytotoxicity in prostate cancer cells

“…Similarly, previous studies have demonstrated that flavonoids inhibit cell growth by inducing S phase cell cycle arrest in prostate cancer cells (19)(20)(21). Flavonoids have also been documented to arrest cell-cycle progression at G0/G1 and G2/M in prostate cancer cells (22)(23)(24). These results indicate that flavonoids may block cell growth at multiple stages of the cell cycle (25).…”