Ribotoxic mycotoxin deoxynivalenol induces G2/M cell cycle arrest via p21Cip/WAF1 mRNA stabilization in human epithelial cells

Deoxynivalenol (DON) and other trichothecene mycotoxins mediate a broad range of epithelial injury including atrophic growth inhibition and inflammation in the human gastrointestinal and respiratory tracts. The purpose of this study was to test the hypothesis that DON alters the cell cycle progress linked to the pathogenesis in the human epithelium. We demonstrated that human epithelial cells underwent G2/M phase arrest in response to DON treatment without significant increase in apoptotic cell death. Moreover, cells deficient in p21 or p53 gene expression showed the attenuated response of G2/M phase arrest by DON. Gene expression of p21 was also induced by DON treatment in a dose-dependent manner with no increase in p53 protein levels, suggesting p53-independent p21 induction. Signaling pathways associated with DON-induced p21 gene expression included PI3 kinase and ERK1/2 MAP kinase cascade. Particularly, ERK1/2 signal was associated with DON-induced p21 mRNA stabilization in the human epithelial cells. Taken together, deoxynivalenol arrested epithelial cell cycle at G2/M phase via elevated p21 gene expression.