Fumonisin B1, a Mycotoxin Contaminant of Cereal Grains, and Inducer of Apoptosis Via the Tumour Necrosis Factor Pathway and Caspase Activation

Fumonisins are mycotoxins produced by Fusarium moniliforme, a prevalent fungus which infects corn or other cereal grains. Fumonisin B1 (FB1) is the most common mycotoxin produced by F. moniliforme, suggesting that it has toxicological significance. The structure of FB1 resembles sphingoid bases and it inhibits ceramide synthase. As sphingoid bases regulate cell growth, differentiation, transformation and apoptosis, it is reasonable to hypothesize that FB1 can also regulate these activities. Previous studies concluded that FB1 induced apoptosis or cell-cycle arrest in CV-1 cells (African green monkey kidney fibroblasts). In this study, we have identified genes that inhibit FB1-induced apoptosis in CV-1 cells and in two primary human cell types (lung fibroblasts and neonatal kidney cells). A baculovirus gene, inhibitor of apoptosis (IAP), protected CV-1 and the human cells from apoptosis. IAP blocks apoptosis which is induced by the tumour necrosis factor (TNF) pathway. Inhibition of interleukin converting enzymes (ICE proteases or caspases) by the baculovirus gene p35 also inhibited FB1-induced apoptosis. FB1 treatment led to cleavage of Rb (retinoblastoma protein) at its C-terminus in CV-1 or human lung cells. As the C-terminus of Rb is cleaved by ICE proteases during apoptosis, this supports an active role for ICE proteases in FB1-induced apoptosis. The tumour suppressor gene p53 was not required for FB1-induced apoptosis because p53−/− primary mouse embryo fibroblasts underwent apoptosis following FB1 treatment. Furthermore, Bcl-2 was not an effective inhibitor of FB1-induced apoptosis in CV-1 or IMR-90 cells. In summary, these results demonstrate that the TNF pathway and caspases plays an important role in FB1-induced apoptosis.