Inhibition of sphingolipid biosynthesis decreases phosphorylated ERK2 in LLC-PK1 cells
2005
Rentz, S.S. | Showker, J.L. | Meredith, F.I. | Riley, R.T.
Fumonisin B1 (FB1) is a fungal toxin produced by Fusarium verticillioides that inhibits ceramide synthase (CS), a key enzyme in the de novo sphingolipid biosynthesis pathway. In LLC-PK1 cells, FB1 inhibits cell proliferation and induces apoptosis, which can be prevented by inhibitors of serine palmitoyltransferase (SPT). Inhibition of SPT prevents the FB1-induced accumulation of free sphinganine, a precursor of ceramide biosynthesis. However, not all of the effects of FB1 in LLC-PK1 cells can be explained solely by the increase in free sphingoid bases. The downstream signaling pathways that are affected by FB1-induced disruption of sphingolipid biosynthesis are not well understood. This study determined, in LLC-PK1 cells, changes in p42 MAP kinase (phosphorylated ERK2 [pERK2]) phosphorylation in response to various inhibitors of key enzymes of the de novo sphingolipid biosynthesis pathway (CS, SPT, and glucosylceramide synthase [GlcCer synthase]). The results show that inhibition of any of the three enzymes caused a similar decrease in the extent of phosphorylation of ERK2 with no reduction in total ERK2. The co-treatment of FB1 (CS inhibitor) with SPT inhibitors or the GlcCer synthase inhibitor had no effect on the FB1-induced reduction in pERK2 phosphorylation, indicating that FB1-mediated changes in phosphorylation of pERK2 was independent of increases in free sphinganine or its metabolites or a reduction in ceramide. Nonetheless, the decrease in pERK2 phosphorylation was dependent on inhibition of de novo sphingolipid biosynthesis. Decreased pERK2 activity could contribute to the physiological effects of FB1 in LLC-PK1 cells that are not due to alteration in pathways modulated by free sphingoid bases and their metabolites but are sensitive to inhibition of glycosphingolipid biosynthesis.
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