Effects of flavonoids on expression of genes involved in cell cycle regulation and DNA replication in human fibroblasts

Abstract

Flavonoids have been studied as potential agents in medicine for many years. Among them, genistein was found to be active in various biological systems, mainly in prevention of cancer. Our recent work supported the idea that genistein also impacts multiple cellular processes in healthy fibroblasts; however, its effects on cell cycle-related pathways remained to be elucidated. Thus, in this work, high throughput screening with microarrays coupled to real-time quantitative Reverse Transcription PCR analyses was employed to study the changes in expression of key genes associated with cell cycle regulation and/or DNA replication in response to genistein, kaempferol, daidzein, and mixtures of genistein and either kaempferol or daidzein. Among them, genistein was found as the most significantly modulating, in a time- and dose-dependent manner, compound of activity of studied genes, whose products are involved in different phases of the cell cycle and/or in regulatory processes important for DNA replication and cell growth. It considerably reduced the efficiency of expression of genes coding for MCM2-7 and MCM10 helicases, as well as some other proteins involved in the S phase control. In addition, genistein caused cell cycle arrest in the G2/M phase, which was accompanied by activation of CDKN1A, CDKN1C, CDKN2A, CDKN2B, CDKN2C, and GADD45A genes, as well as down-regulation of several mRNAs specific for this stage, demonstrated by transcriptomic assessments. We believe that studies described in this paper will be helpful in elucidating molecular mechanisms of action of genistein as modulator of cell cycle and inhibitor of DNA replication in humans.

Abnormal Sphingolipid World in Inflammation Specific for Lysosomal Storage Diseases and Skin Disorders

“…The latest findings of our group allowed us to learn about a putative flavonoid targetome which is responsible for significant molecular processes, such as an impairment of the production and enhancement of degradation of glycosaminoglycans and sphingolipids [ 204 , 205 , 206 ], or cell cycle and DNA replication regulation [ 207 ]. Transcriptomics analyses indicated that selected flavonoids influence the expression of several genes involved in cellular metabolism.…”

Cell cycle is disturbed in mucopolysaccharidosis type II fibroblasts, and can be improved by genistein

“…Since genistein was found to modulate expression of genes involved in the regulation of the cell cycle [12], we asked whether this isoflavone may influence the effects observed in . 1).…”

“…Interestingly, similar studies with global analyses of gene expression indicated that genistein can modulate expression of genes coding for proteins involved in DNA replication and cell cycle regulation, including MCM2-7, CDKN1A, CDKN1C, CDKN2A, CDKN2B, CDKN2C and GADD45A [12]. In this light, we aimed to investigate whether cell cycle is affected in MPS fibroblasts and if genistein can influence this process in these cells.…”

Investigating the Effect of Fennel and Cinnamon Combined Extract on Spermatogenesis and Testis Tissues in Busulfan Induced Infertile Rats

“…According to the findings of recent studies, flavonoids could restrain DNA replication and inhibit cell division, as well as stimulate apoptosis by affecting cell DNA. 32 Garawani et al reported that the consumption of fennel oil in etoposide defective rats caused reduction of sperm defects and increased mature sperm production, which was due to the anti-oxidant properties of the fennel extract. 33 The findings of Garawani et al's study about the effect of fennel on spermatogenesis are contradictory to the findings of this study.…”