Sphingolipid Perturbations as Mechanisms for Fumonisin Carcinogenesis

To the best of our knowledge, one or more authors of this paper were federal employees when contributing to this work.\ud This is the publisher’s final pdf. The published article is copyrighted by the National Institute of Environmental Health Sciences (NIEHS) and can be found at: http://ehp.niehs.nih.gov/.There is a great deal of evidence that altered sphingolipid metabolism is associated with fumonisin-induced\ud animal diseases including increased apoptotic and oncotic necrosis, and carcinogenesis in\ud rodent liver and kidney. The biochemical consequences of fumonisin disruption of sphingolipid\ud metabolism most likely to alter cell regulation are increased free sphingoid bases and their\ud 1-phosphates, alterations in complex sphingolipids, and decreased ceramide (CER) biosynthesis.\ud Because free sphingoid bases and CER can induce cell death, the fumonisin inhibition of CER\ud synthase can inhibit cell death induced by CER but promote free sphingoid base-induced cell death.\ud Theoretically, at any time the balance between the intracellular concentration of effectors that\ud protect cells from apoptosis (decreased CER, increased sphingosine 1-phosphate) and those that\ud induce apoptosis (increased CER, free sphingoid bases, altered fatty acids) will determine the\ud cellular response. Because the balance between the rates of apoptosis and proliferation is important\ud in tumorigenesis, cells sensitive to the proliferative effect of decreased CER and increased\ud sphingosine 1-phosphate may be selected to survive and proliferate when free sphingoid base\ud concentration is not growth inhibitory. Conversely, when the increase in free sphingoid bases\ud exceeds a cell’s ability to convert sphinganine/sphingosine to dihydroceramide/CER or their\ud sphingoid base 1-phosphate, then free sphingoid bases will accumulate. In this case cells that are\ud sensitive to sphingoid base-induced growth arrest will die and insensitive cells will survive. If the\ud cells selected to die are normal phenotypes and the cells selected to survive are abnormal, then\ud cancer risk will increase