title: Limoniastrum guyonianum aqueous gall extract induces apoptosis in human cervical cancer cells involving p16 INK4A re-expression related to UHRF1 and DNMT1 down-regulation.
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.
authors.affiliation: UMR CNRS 7213, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, 74 Route du Rhin, CS 60024, Illkirch, Cedex F-67401, France.
authors.forename: Mounira
authors.initials: M
authors.lastname: Krifa
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Alhosin
authors.forename: Christian D
authors.initials: CD
authors.lastname: Muller
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gies
authors.forename: Leila
authors.initials: L
authors.lastname: Chekir-Ghedira
authors.forename: Kamel
authors.initials: K
authors.lastname: Ghedira
authors.forename: Yves
authors.initials: Y
authors.lastname: Mély
authors.forename: Christian
authors.initials: C
authors.lastname: Bronner
authors.forename: Marc
authors.initials: M
authors.lastname: Mousli
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D047311:Luteolin / Q000494:pharmacology; D053147:Plant Exudates / Q000737:chemistry / Q000494:pharmacology*; D010941:Plant Tumors; D064028:Tracheophyta / Q000737:chemistry*; D044767:Ubiquitin-Protein Ligases; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D022762:CCAAT-Enhancer-Binding Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D053147:Plant Exudates; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases; D047311:Luteolin