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.

Foodborne aflatoxin B-1 (AFB(1)) 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. AFB(1) 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 AFB(1) alone and reduced by OTA. With marginal cell death responses, AFB(1) induced p53-mediated S phase arrest and cell cycle-regulating target genes, which was completely suppressed by OTA. Although enterocyte-dominant CYP3A5 counteracted AFB(1)-induced DNA damage, expression of CYP3A5 was decreased by OTA or AFB(1). Instead, OTA enhanced expression of another metabolic inactivating enzyme CYP3A4, attenuation of formation of AFB(1)-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 AFB(1)-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.