Abstract
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.
Highlights
Several food-contaminating mycotoxins including aflatoxins and ochratoxins have been identified by the International Agency for Research in Cancer (IARC) as harmful carcinogens that potently promote tumor development in several organs including the liver and kidney of mammals [1, 2]
Based on the assumption that genotoxic stress induces DNA damage via p53-linked pathways, p53promoted murine double minute 2 homolog (Mdm2) expression was monitored in human intestinal cancer cells exposed to the genotoxic mycotoxins
In response to aflatoxin B1 (AFB1) treatment, Mdm2 promoter activity was increased in a dosedependent manner (Figure 1B)
Summary
Several food-contaminating mycotoxins including aflatoxins and ochratoxins have been identified by the International Agency for Research in Cancer (IARC) as harmful carcinogens that potently promote tumor development in several organs including the liver and kidney of mammals [1, 2]. Aflatoxin B1 (AFB1) has been regarded as a representative orally ingested carcinogen in humans, and is classified as a Group 1 carcinogen by the IARC [3, 4]. Ochratoxin A (OTA) produced by Aspergillus and Penicillium fungi has been classified as a possible human carcinogen (Group 2B) by the IARC [9, 10]. The major target organ of OTA toxicity in experimental animals is the kidney, and endemic nephropathies affecting livestock as well as humans have been associated with www.impactjournals.com/oncotarget
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