TY - JOUR
T1 - Resveratrol induces DNA damage in colon cancer cells by poisoning topoisomerase II and activates the ATM kinase to trigger p53-dependent apoptosis
AU - Demoulin, Benjamin
AU - Hermant, Maryse
AU - Castrogiovanni, Cédric
AU - Staudt, Catherine
AU - Dumont, Patrick
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Colon cancer
KW - DNA damage
KW - P53
KW - Resveratrol
KW - Topoisomerase II
UR - http://www.scopus.com/inward/record.url?scp=84929993798&partnerID=8YFLogxK
U2 - 10.1016/j.tiv.2015.04.015
DO - 10.1016/j.tiv.2015.04.015
M3 - Article
AN - SCOPUS:84929993798
SN - 0887-2333
VL - 29
SP - 1156
EP - 1165
JO - Toxicology in vitro
JF - Toxicology in vitro
IS - 5
ER -