Fumonisin

8: Chem Biol Interact 2003 Jun 15;145(3):297-309

Increased susceptibility of renal epithelial cells to TNFalpha-induced apoptosis following treatment with fumonisin B(1).

Johnson VJ, He Q, Kim SH, Kanti A, Sharma RP.

Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, 30602 7389, Athens, GA, USA

Previous studies have shown that tumor necrosis factor alpha (TNFalpha) is involved in the pathogenic events following exposure to fumonisin B(1) (FB(1)), a potent inhibitor of ceramide synthase and sphingolipid biosynthesis. The intimate role of sphingolipid mediators in TNFalpha signaling and cellular death suggests that FB(1) may alter the sensitivity of cells to TNFalpha-induced apoptosis. We tested the hypothesis that FB(1) treatment will increase the sensitivity of porcine renal epithelial cells to TNFalpha. Porcine renal epithelial cells (LLC-PK(1)) were treated with FB(1) for 48 h prior to treatment with TNFalpha. A dose-dependent increase in TNFalpha-induced apoptosis was observed in cells pretreated with FB(1). Cells treated with FB(1) showed increased DNA fragmentation and terminal uridine nucleotide end labeling in response to TNFalpha treatment. FB(1) increased DNA synthesis and resulted in cell cycle arrest in the G(2)/M phase of the cell cycle. Flow cytometric analysis of the cell cycle indicated that TNFalpha predominantly killed cells in the G(2)/M phase. The activation of JNK, a mitogen-activated protein kinase (MAPK), was increased following 48 h exposure to FB(1). Phosphorylation of p38 and ERK remained unchanged following treatment with FB(1). FB(1) also increased free sphingoid base levels under identical treatment conditions. Results suggest that FB(1) increased free sphingoid base levels and the population of cells in the G(2)/M phase. This population was shown to be most susceptible to TNFalpha-induced apoptosis. Phosphorylation of pro-apoptotic JNK may play an important role in these effects.

PMID: 12732456

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