Limoniastrum guyonianum aqueous gall extract induces apoptosis in human cervical cancer cells involving p16 INK4A re-expression related to UHRF1 and DNMT1 down-regulation.

Mounira Krifa,Mahmoud Alhosin,Kamel Ghedira,Christian D Muller,Marc Mousli,Christian Bronner,Leila Chekir-Ghedira,Yves Mély,Jean-Pierre Gies

doi:10.1186/1756-9966-32-30

Abstract

Several reports have described the potential effects of natural compounds as anti-cancer agents in vitro as well as in vivo. The aim of this study was to evaluate the anti-cancer effect of Limoniastrum guyonianum aqueous gall extract (G extract) and luteolin in the human cervical cancer HeLa cell line, and, if so, to clarify the underlying mechanism. Our results show that G extract and luteolin inhibited cell proliferation and induced G2/M cell cycle arrest in a concentration and time-dependent manner. Both natural products induced programmed cell death as confirmed by the presence of hypodiploid G0/G1 cells. These effects are associated with an up-regulation of the expression of the tumor suppressor gene p16INK4A and a down-regulation of the expression of the anti-apoptotic actor UHRF1 and its main partner DNMT1. Moreover, G extract- and luteolin-induced UHRF1 and DNMT1 down-regulation is accompanied with a global DNA hypomethylation in HeLa cell line. Altogether our results show that G extract mediates its growth inhibitory effects on human cervical cancer HeLa cell line likely via the activation of a p16INK4A -dependent cell cycle checkpoint signalling pathway orchestrated by UHRF1 and DNMT1 down-regulation.

Highlights

Natural products derived from plants have received extensive attention as potential anti-cancer agents over few decades
Aqueous gall extract and luteolin induce UHRF1 and DNA methyltransferase1 (DNMT1) down-regulation and p16INK4A up-regulation associated with a reduced global DNA methylation The present study was undertaken to investigate the effect of G extract on the expression of UHRF1/DNMT1 tandem known to be involved in gene expression regulation via DNA methylation [9,11]
A recently published study has shown that UHRF1 depletion in cancer cells causes G2/M cell cycle arrest and apoptosis accompanied with phosphorylation of cyclin-dependent kinase 1 (CDK1) [37] which is in agreement with our present data

Summary

Introduction

Natural products derived from plants have received extensive attention as potential anti-cancer agents over few decades. Most of current anti-cancer drugs such as camptothecin, vincristine, taxol, etoposide and paclitaxel are plant-derived compounds [1,2]. A hypermethylation of the tumor suppressor gene p16INK4A at its CpG-rich promoter regions and subsequent inactivation of the p16INK4A gene have been reported in several haematological and solid cancers [6,7]. This hypermethylation targets the expression of specific genes involved in the DNA damage response including, the retinoblastoma protein (pRB) [8].

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