Sphingolipid Perturbations as Mechanisms for Fumonisin Carcinogenesis

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.

Ceramide Synthase Inhibition by Fumonisin B1 Causes Accumulation of 1-Deoxysphinganine

“…As a consequence of this inhibition, the substrates sphinganine (Sa) and, usually to a lesser extent, sphingosine (So), accumulate and are often diverted to sphinganine 1-phosphate (Sa1P) and sphingosine 1-phosphate (S1P), respectively (7), while the product N-acylsphinganines (dihydroceramides), N-acylsphingosines (ceramides, Cer), and more complex sphingolipids decrease (5, 7). This disruption of sphingolipid metabolism has been proposed to be responsible for the toxicity, and possibly carcinogenicity, of FB, based on mechanistic studies with cells in culture (5,(7)(8)(9). This has been borne out by a number of animal feeding studies that have correlated the elevation of Sa in blood, urine, liver, and kidney with liver and kidney toxicity (4, 7, 10, 11).…”

“…ple mediators may participate (7,9). Nonetheless, inhibition of serine palmitoyltransferase (SPT), the initial enzyme of de novo sphingolipid biosynthesis, reverses the increased apoptosis and altered cell growth induced by FB 1 treatment (12)(13)(14)(15)(16)(17)(18)(19).…”

Advances in Mycotoxin Research: Public Health Perspectives

“…It is well known that FB 1 inhibits sphingolipid biosynthesis leading to elevation of sphinganine (Sa) levels as well as the ratio of Sa to sphingosine (So) (Merrill and others ; Wang and others ; Riley and others ). Hence, the Sa:So ratio in blood and urine has been suggested as a useful biomarker for dietary exposure to fumonisins (Qiu and Liu ; Cai and others ).…”

Biosynthesis and Molecular Genetics of Fungal Secondary Metabolites, Volume 2

“…Fumonisin is non-genotoxic and acts primarily via inhibition of ceramide biosynthesis. Fumonisins are structurally similar to sphinganine, and inhibit dihydroceramide synthase [222]. The perturbation of sphingolipids directly impacts the membrane properties and consequently on the function of certain membrane proteins.…”