Disruption of sphingolipid metabolism and stimulation of DNA synthesis by fumonisin B1. A molecular mechanism for carcinogenesis associated with Fusarium moniliforme.

Abstract

Consumption of grains contaminated with Fusarium moniliforme (Sheldon) causes liver cancer in rats and has been correlated with esophageal cancer in humans. The causative agents are believed to be a family of compounds known as fumonisins, which bear remarkable structural resemblances to sphingosine and sphinganine, the long-chain (sphingoid) base backbones of sphingolipids. Recently, fumonisin B1 has been shown to block de novo synthesis of sphingolipids by inhibiting sphingosine (sphinganine) N-acyltransferase, which leads to accumulation of sphingoid bases. Because the exogenous addition of sphingosine and sphingosine 1-phosphate to Swiss 3T3 cells has been shown to stimulate DNA synthesis (Zhang, H., Buckley, N.E., Gibson, K., and Spiegel, S. (1990) J. Biol. Chem. 265, 76-81; Zhang, H., Desai, N.N., Olivera, A., Seki, T., Brooker, G., and Spiegel, S. (1991) J. Cell Biol. 114, 155-167), we hypothesized that fumonisins might stimulate DNA synthesis by disrupting sphingolipid metabolism. Fumonisin B1 caused accumulation of sphinganine and sphingosine in Swiss 3T3 fibroblasts and, as occurred when these sphingoid bases were added exogenously, stimulated thymidine incorporation into DNA and augmented the mitogenic effect of insulin in a concentration-dependent manner. The mechanism underlying the mitogenic effect of fumonisin B1 was further investigated by using beta-fluoroalanine to block the initial step of sphingolipid biosynthesis catalyzed by serine palmitoyltransferase. beta-Fluoroalanine reduced sphingoid base accumulation in fumonisin B1-treated fibroblasts and inhibited fumonisin B1-stimulated DNA synthesis, but had no effect on mitogenesis when added alone. Fumonisin B1 did not cause accumulation of sphinganine 1-phosphate; therefore, it appears that sphingoid bases per se can stimulate DNA synthesis. To prove that the 1-phosphate is not obligatory, a 1-deoxysphinganine was synthesized, and it was as potent as sphinganine in stimulating DNA synthesis. These results establish that fumonisin B1 is mitogenic via accumulation of sphingoid bases rather than inhibition of complex sphingolipid biosynthesis per se. Because mitogens can often affect cell transformation, this provides a plausible molecular mechanism to explain the carcinogenicity of fumonisins.