title: Resveratrol induces DNA damage in colon cancer cells by poisoning topoisomerase II and activates the ATM kinase to trigger p53-dependent apoptosis.
abstract: Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural polyphenol synthesized by various plants such as grape vine. Resveratrol (RSV) is a widely studied molecule, largely for its chemopreventive effect in different mouse cancer models. We propose a mechanism underlying the cytotoxic activity of RSV on colon cancer cells. Our data show that resveratrol induces apoptosis, as observed by the cleavage of PARP-1 and chromatin condensation. We show that the tumor suppressor p53 is activated in response to RSV and participates to the apoptotic process. Additionally, we show that HCT-116 p53 wt colon carcinoma cells are significantly more sensitive than HCT-116 p53-/- cells to RSV. RSV induces DNA damage including double strand breaks, as evidenced by the presence of multiple γ-H2AX foci in 50% of cells after a 24 h treatment with 25 μM RSV. The formation of DNA damage does not appear to rely on a pro-oxidant effect of the molecule, inhibition of topoisomerase I, or DNA intercalation. Rather, we show that DNA damage is the consequence of type II topoisomerase poisoning. Exposure of HCT-116 cells to RSV leads to activation of the Ataxia Telangiectasia Mutated (ATM) kinase, and ATM is required to activate p53.
authors.affiliation: Laboratory of Cell Biology, Institute of Life Sciences, Université catholique de Louvain, Croix du Sud 5, Louvain-la-Neuve 1348, Belgium.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Demoulin
authors.affiliation: Laboratory of Cell Biology, Institute of Life Sciences, Université catholique de Louvain, Croix du Sud 5, Louvain-la-Neuve 1348, Belgium.
authors.forename: Maryse
authors.initials: M
authors.lastname: Hermant
authors.affiliation: Laboratory of Cell Biology, Institute of Life Sciences, Université catholique de Louvain, Croix du Sud 5, Louvain-la-Neuve 1348, Belgium.
authors.forename: Cédric
authors.initials: C
authors.lastname: Castrogiovanni
authors.affiliation: Laboratory of Cell Biology, Institute of Life Sciences, Université catholique de Louvain, Croix du Sud 5, Louvain-la-Neuve 1348, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Staudt
authors.affiliation: Laboratory of Cell Biology, Institute of Life Sciences, Université catholique de Louvain, Croix du Sud 5, Louvain-la-Neuve 1348, Belgium. Electronic address: patrick.dumont@uclouvain.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Dumont
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D004250:DNA Topoisomerases, Type II; D000077185:Resveratrol
keywords: Apoptosis; Colon cancer; DNA damage; Resveratrol; Topoisomerase II; p53