Genistein suppresses the proliferation of telomerase-negative cells.

Chuan‐Chuan Lin,Shu‐Chun Teng,Meng‐Hsun Hsieh

doi:10.1002/fsn3.382

Abstract

In both tumor and yeast cells that lack telomerase, telomeres are maintained via an alternative recombination mechanism. In this study, we tested genistein, a potential TOP2 inhibitor required for telomere–telomere recombination, on the repression of telomere–telomere recombination. Genistein on the repression of type II recombination on a tlc1 yeast strain was examined by the telomeric DNA structures using Southern blot analysis. Telomere patterns of freshly dissected tlc1 spores containing an empty plasmid (pYES2) or a yeast TOP2 (yTOP2) plasmid were analyzed. The results indicated that the reintroduction of TOP2 recovered the type II pattern, implying genistein in the blockage of type II survivors in the tlc1 strain. The effects of genistein on both tlc1 and tlc1 rad 51 strains in liquid and solid mediums were also examined. Finally, treatment of 10 μmol/L of genistein showed inhibitory effect on the growth of telomerase‐negative U2OS alternative lengthening of telomere (ALT) cells, but not in telomerase‐positive HCT116 cells. These results provide evidences that the inhibitory effects of genistein on telomerase‐negative cells depend on type II recombination pathway in yeast and the ALT pathway in human tumors.

Highlights

Telomeres, the protein–DNA structures found at the natural ends of eukaryotic chromosomes, are required to protect chromosomes from degradation and end-to-end fusion and to facilitate their complete replication
In order to investigate the molecular mechanism of telomere–telomere recombination, we have identified factors required for this pathway (Teng and Zakian 1999; Teng et al 2002; Tsai et al 2002)
We demonstrate that TOP2 and TOP3a are required for telomere–telomere recombination in yeast and in alternative lengthening of telomere (ALT)-type cancers (Tsai et al 2006; Hsieh et al 2015)

Summary

Introduction

The protein–DNA structures found at the natural ends of eukaryotic chromosomes, are required to protect chromosomes from degradation and end-to-end fusion and to facilitate their complete replication. Hundreds of studies have reported the antitumor activities of isoflavones in its mechanism of action in normal and malignant human and animal cells, animal models, in vitro experiments, or phase I/II clinical trials (Magee et al 2004; Cornwell et al 2004). In addition to their actions as partial estrogen agonists or antagonists, genistein (4sym, 5, 7-trihydroxyisoflavone), the most well-studied isoflavone in the literatures, has been shown to inhibit protein tyrosine kinase and topoisomerase I and II (Akiyama et al 1987; Markovits et al 1989; Boege et al 1996). We showed that an isoflavone and potential topoisomerase inhibitor, genistein, prevents telomere recombination in yeast and suppresses cell proliferation in ALT-type cancers

Materials and Methods

Results and Discussion

Concluding remarks