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 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.
Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan, South Korea.
Juil
J
Kim
Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan, South Korea.
Seong-Hwan
SH
Park
Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan, South Korea.
Kee Hun
KH
Do
National Institute of Animal Science, RDA, Wanju, South Korea.
Dongwook
D
Kim
Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan, South Korea.|Research Institute for Basic Sciences and Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Pusan, South Korea.
Yuseok
Y
Moon
D016604:Aflatoxin B1 / Q000737:chemistry*; D002273:Carcinogens / Q000737:chemistry; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002469:Cell Separation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005434:Flow Cytometry; D016678:Genome; D045325:HCT116 Cells; D006801:Humans; D007414:Intestinal Neoplasms / Q000378:metabolism*; D009153:Mutagens; D009793:Ochratoxins / Q000737:chemistry*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002273:Carcinogens; D018736:DNA Adducts; D009153:Mutagens; D009793:Ochratoxins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C025589:ochratoxin A; D016604:Aflatoxin B1; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
Mdm2 protein; aflatoxin; intestinal cancer cells; ochratoxin; p53 protein