Interference with mutagenic aflatoxin B1-induced checkpoints through antagonistic action of ochratoxin A in intestinal cancer cells: a molecular explanation on potential risk of crosstalk between carcinogens
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Juil Kim1, Seong-Hwan Park1, Kee Hun Do1, Dongwook Kim2, Yuseok Moon1,3
1Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan, South Korea
2National Institute of Animal Science, RDA, Wanju, South Korea
3Research Institute for Basic Sciences and Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Pusan, South Korea
Yuseok Moon, e-mail: firstname.lastname@example.org
Keywords: aflatoxin, ochratoxin, intestinal cancer cells, p53 protein, Mdm2 protein
Received: January 25, 2016 Accepted: April 05, 2016 Published: April 22, 2016
Foodborne aflatoxin B1 (AFB1) and ochratoxin A (OTA) cause genotoxic injury and subsequent tumor formation. As a biomarker of oncogenic stimulation by genotoxic mycotoxins, p53-triggered Mdm2 was assessed in intestinal cancer cells. AFB1 increased Mdm2 reporter expression in a dose-dependent manner. However, this was strongly antagonized by OTA treatment. As a positive transcription factor of Mdm2 expression, p53 levels were also increased by AFB1 alone and reduced by OTA. With marginal cell death responses, AFB1 induced p53-mediated S phase arrest and cell cycle-regulating target genes, which was completely suppressed by OTA. Although enterocyte-dominant CYP3A5 counteracted AFB1-induced DNA damage, expression of CYP3A5 was decreased by OTA or AFB1. Instead, OTA enhanced expression of another metabolic inactivating enzyme CYP3A4, attenuation of formation of AFB1-DNA adduct and p53-mediated cell cycle checking responses to the mutagens. Finally, the growth of intestinal cancer cells exposed to the mycotoxin mixture significantly exceeded the expected growth calculated from that of cells treated with each mycotoxin. Although AFB1-induced mutagen formation was decreased by OTA, interference with checkpoints through antagonistic action of OTA may contribute to the survival of tumor cells with deleterious mutations by genotoxic mycotoxins, potently increasing the risk of carcinogenesis.
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