title: Luteolin induces apoptosis in BE colorectal cancer cells by downregulating calpain, UHRF1, and DNMT1 expressions.
abstract: In this study, we have investigated the effects of luteolin on colorectal cancer cells. Our results demonstrate that luteolin is able to induce cytotoxicity and cell cycle perturbation in a dose-dependent manner. By triggering poly(ADP-ribose) polymerase (PARP) cleavage, this molecule is able to induce the apoptosis of BE colorectal cancer cells. We have also studied the potential involvement of calpains in the proapoptotic effects of luteolin. Our data show that luteolin exhibits moderate inhibitory activity against calpain. Thus, treatment of these cells with both luteolin and the calpain inhibitor MDL 28170 causes an increase in the luteolin-induced apoptosis as proved by the enhancement of 89- and 26-kDa PARP fragments. This effect is concomitant with the downregulation of the DNA methyltransferase 1 (DNMT1) expression and the epigenetic integrator ubiquitin-like containing PHD Finger 1 (UHRF1). As a result, luteolin induces an upregulation of a tumor suppressor gene: p16(INK4A). This study further proposes that calpain might be involved in the epigenetic code inheritance by regulating the epigenetic integrator UHRF1. We conclude from these results that targeting calpain, UHRF1, and DNMT1 using luteolin could be an interesting way to prevent and/or treat colorectal cancers.
authors.affiliation: a Unité de Pharmacognosie/Biologie Moléculaire, Faculté de Pharmacie de Monastir, Université de Monastir , Monastir , Tunisie.
authors.forename: Mounira
authors.initials: M
authors.lastname: Krifa
authors.forename: Ludovic
authors.initials: L
authors.lastname: Leloup
authors.forename: Kamel
authors.initials: K
authors.lastname: Ghedira
authors.forename: Marc
authors.initials: M
authors.lastname: Mousli
authors.forename: Leila
authors.initials: L
authors.lastname: Chekir-Ghedira
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047311:Luteolin / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004151:Dipeptides; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases; D011065:Poly(ADP-ribose) Polymerases; D002154:Calpain; D047311:Luteolin; C058076:calpain inhibitor III