Aflatoxin B1 induces S phase arrest by upregulating the expression of p21 via MYC, PLK1 and PLD1

Aflatoxin B-1 (AFB(1)), a member of the aflatoxin family, is a common contaminant in foods and feeds, and AFB(1) exposure is associated with various clinical conditions. Thus far, research on the toxicity of AFB(1) has mainly focused on its induction of liver cancer, but little research has been reported on renal toxicity, especially with regards to the underlying molecular mechanisms. In this study, we found that AFB(1) treatment significantly induced kidney damage and reduced kidney weight. The human kidney cell line HEK293T was used to further study the molecular mechanism of the toxicity of AFB(1) to kidney cells. We found that AFB(1) significantly and dose-dependently induced S phase arrest and upregulated p21 mRNA and protein expression. Upstream of p21, three negative regulators, PLK1, MYC, and PLD1, were significantly downregulated under AFB(1). treatment. Consistently, p21 was upregulated, and PLK1, MYC and PLD1 were downregulated in mouse kidney after AFB(1) treatment. Interestingly, AFB(1) also decreased the physical interaction between PLK1 and MYC and weakened the stability of the MYC protein. Importantly, overexpression of PLK1, MYC and PLD1 significantly blocked the upregulation of p21 and attenuated the S phase arrest caused by AFB(1). In summary, AFB(1) markedly induces kidney damage and strongly induces S phase arrest by upregulating the expression of p21 via PLK1, PLD1 and MYC, which represents a noval mechanism of the renal toxicity of AFB(1).