Apoptosis is a form of cell death that occurs normally during development, in response to cellular or DNA damage, and when cells are dislodged from their natural environment. During apoptosis, the nucleus condenses, and the cell is packaged into small pieces that are eventually engulfed by macrophages and destroyed. Since DNA damage can lead to cancer-causing mutations, apoptosis is one of the body’s most important surveillance mechanisms for eliminating cells that could give rise to cancer. If cancer does develop, apoptosis may still protect against metastasis by killing cancer cells as they dislodge from the primary tumor and spread to other tissues. Chemotherapy and radiation act primarily by causing DNA damage in cancer cells, leading to apoptosis. Loss of apoptotic responses (such as by mutation of the pro-apoptotic gene p53 or overexpression of the anti-apoptotic gene Bcl-2) contributes to the development, progression and drug resistance of cancer. Understanding the mechanisms that regulate apoptosis is a critical goal that may identify genetic risk factors and provide new approaches for the detection, monitoring and treatment of cancer.

Our studies indicate that the enzymes of S1P metabolism have a strong influence on apoptosis. For example, S1P lyase depletes cells of S1P, making them more susceptible to apoptosis when treated with chemotherapy and radiation. Conversely, sphingosine kinase functions as an oncogene by generating more S1P, thereby stimulating cell proliferation and inhibiting apoptosis. By regulating the cellular response to chemotherapy and radiation, the enzymes of S1P metabolism may, thus, be ideal therapeutic targets for cancer therapy.

The cellular processes governed by S1P (cell migration, proliferation, and apoptosis) are also critically important in the normal expansion, reduction, reorganization and differentiation of individual cell populations during embryonic development. S1P metabolism is conserved throughout evolution, making it possible to study S1P pathways using simple model systems such as yeast, nematodes (shown above) and fruitflies. What do invertebrate models, far removed from humans in the evolutionary tree, have to offer in the elucidation of S1P signaling and metabolism and its relevance to human disease? By studying S1P metabolism in genetic model systems in which many important signaling pathways are well-characterized, we may better understand how S1P mediates its effects on cells and tissues. By generating mutants defective in S1P synthesis or degradation and examining the phenotypes resulting from altered S1P metabolism down to the cellular and molecular level, we may learn how S1P influences universal processes including lipid and protein trafficking, cell fate and migration and may thereby impact upon human disease. Since a large proportion of disease-related genes are conserved in these simple organisms, information gained by studying S1P metabolism in developmental model systems may also pertain to disease states in which S1P signaling has been implicated such as cancer, cardiovascular disease, and sterility. For example, we have found that loss of the S1P lyase gene in the fruitfly Drosophila melanogaster results in destruction of muscles and reproductive organs, and withering of the reproductive tract in the nematode Caenorhabditis. elegans. These “disappearing organs” are the result of waves of cellular apoptosis within the corresponding tissues, indicating how important S1P metabolism is for cell and organ survival.