The effects of exogenous sphingolipids have been well documented in many in vitro studies, but the mechanisms of how sphingolipid metabolites suppress tumor formation in vivo are less defined. A somewhat simplified concept of chemopre-vention with sphingolipids is the hypothesis that exogenous sphingolipids can provide the bioactive sphingolipid metabolites lacking in cancer cells that have a defect in the generation of bioactive metabolites due to reduced sphingomyeli-nase activity or enhanced removal of bioactive metabolites. This is based on many in vitro observations demonstrating that cell-permeable sphingolipid metabolites mimic the effect of endogenously generated metabolites and therefore could reverse the unlimited growth capacity of cancer cells. However, the molecular diversity of tumor cells even in the same patient and the number of already identified intracellular targets of sphingolipids that are involved in some aspects of carcinogenesis suggest that there are likely more pathways of how exogenous sphingolipids prevent tumor formation.
In our studies using orally administered sphingolipids to prevent chemically induced colon cancer in CF1 mice, we found that a reversal of carcinogen-induced increase of proliferation and reduced rate of apoptosis rather than the induction of apoptosis per se may be the important event.666772 This reversal was not limited to a specific structure of sphingolipids but was seen after administration of all complex sphingolipids from milk and soy. To determine how sphingolipids cause this "growth normalization," we evaluated the effect of sphingolipids on one of the earliest events in colon carcinogenesis, the dysregulation of P-catenin. P-Catenin is a cell adhesion protein that connects E-cadherin or other membrane proteins to the actin cytoskeleton via a-catenin.88 P-Catenin also functions as a signaling molecule in developmental systems,89 and in the cellular response to growth stimulation through the Wnt pathway or activated growth factor receptors.8890 Stabilized P-catenin accumulates in the cytosol, translocates to the nucleus, and activates transcription of genes that are involved in proliferation, adhesion, and migration such as cyclin D1, c-myc, and E-cadherin (see www.stan-ford.edu/~rnusse/wntwindow.html for an updated list of targets). P-Catenin metabolism is regulated by the adenomatous polyposis coli (APC) gene product that is mutated in 40 to 80% of sporadic colon cancer.70 71 APC mutations seem to be crucial for the development of dysplastic ACF that will progress toward adenoma and adenocarcinoma both in humans and in chemically induced colon cancer in rodents,91 rather than regress as most of the hyperplastic ACF. All cells in Min mice are heterozygous for APC and tumor formation is preceded by the loss of the APC wild-type allele, and the deregulation of P-catenin. The dysreg-ulation of P-catenin is therefore a critical early event, common in all our rodent models, and also important in human colon cancer, identifying P-catenin as target for chemopreventive drugs. However, P-catenin may not necessarily be critical in later stages after the addition of further mutations render P-catenin superfluous.
In Min mice that were fed the control AIN 76A diet alone and developed a large number of intestinal tumors, we found a high expression of cytosolic P-catenin in intestinal sections as determined by fluorescence immunohisto-chemistry. Min mice that were fed sphingolipid supplements and that had developed only a small number of tumors displayed mostly membrane-associated P-catenin. This is the localization found in the genetic background mice, suggesting a reversal of aberrant P-catenin expression by sphingolipids.72 The same effect of exogenous sphingolipids could be seen in vitro in human colon cancer cell lines that also carry an APC mutation, and stably overexpress cytosolic P-catenin. Both sphingosine and ceramides in nontoxic concentrations reduced cytosolic and nuclear P-catenin.72 This is a critical step in cancer prevention because removal of cytosolic and nuclear P-catenin has been shown to reverse the transformed properties of cells92 and suggests that the reversal of critical early changes in colon carcinogenesis may be the key event in cancer prevention. In Figure 25.5, the central role for P-catenin and its regulation are depicted. Interestingly, key proteins that regulate P-catenin metabolism such as Akt, GSK-3P, EGFR, and PKC isozymes are directly or indirectly regulated by sphingolipid metabolites. Although it is possible, even likely, that this is not the only mechanism by which sphingolipids prevent cancer, given the importance of increased cytosolic P-catenin not only in the etiology of colon cancer but also in breast, skin, prostate, and kidney cancer, the determination of the mechanisms how sphingolipids regulate P-catenin and its role in cancer prevention and possible use as a marker for sphingolipid efficacy both in vitro and in vivo is warranted.
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