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Sphingolipid Perturbations as Mechanisms for Fumonisin Carcinogenesis

Ronald T. Riley, Evaristus Enongene, Kenneth A. Voss, William P. Norred, Filmore I. Meredith, Raghubir P. Sharma, Jan Spitsbergen, David E. Williams, David B. Carlson and Alfred H. Merrill, Jr.
Environmental Health Perspectives
Vol. 109, Supplement 2 (May, 2001), pp. 301-308
DOI: 10.2307/3435022
Stable URL: http://www.jstor.org/stable/3435022
Page Count: 8
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Sphingolipid Perturbations as Mechanisms for Fumonisin Carcinogenesis
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Abstract

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.

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