There is a great deal of evidence that altered
sphingolipid metabolism is associated with
fumonisin-induced
animal diseases including increased apoptotic and oncotic
necrosis, and
carcinogenesis in rodent liver and kidney. The biochemical consequences of
fumonisin disruption of
sphingolipid metabolism most likely to alter cell regulation are increased free sphingoid bases and their 1-phosphates, alterations in complex
sphingolipids, and decreased
ceramide (CER) biosynthesis. Because free sphingoid bases and CER can induce cell death, the
fumonisin inhibition of CER synthase can inhibit cell death induced by CER but promote free sphingoid base-induced cell death. Theoretically, at any time the balance between the intracellular concentration of effectors that protect cells from apoptosis (decreased CER, increased
sphingosine 1-
phosphate) and those that induce apoptosis (increased CER, free sphingoid bases, altered
fatty acids) will determine the cellular response. Because the balance between the rates of apoptosis and proliferation is important in
tumorigenesis, cells sensitive to the proliferative effect of decreased CER and increased
sphingosine 1-phosphate may be selected to survive and proliferate when free sphingoid base concentration is not growth inhibitory. Conversely, when the increase in free sphingoid bases exceeds a cell's ability to convert
sphinganine/
sphingosine to
dihydroceramide/CER or their sphingoid base 1-phosphate, then free sphingoid bases will accumulate. In this case cells that are sensitive to sphingoid base-induced growth arrest will die and insensitive cells will survive. If the cells selected to die are normal phenotypes and the cells selected to survive are abnormal, then
cancer risk will increase.