Abstract ED01-02: Sphingolipid biodiversity and cancer: an endless source of surprises in cell regulation and novel strategies for cancer chemoprevention and chemotherapy

ED01-02

Sphingolipids are found in essentially all eukaryotes and some prokaryotes and viruses where they influence cell structure, signaling, and interactions with the extracellular environment. The structural diversity of sphingolipids is mind-bogglingly complex due to the combinatorial possibilities for subspecies variation in the lipid backbones (sphingoid base and N-acyl-derivatives, i.e., “ceramides”) and headgroups.

Early comparisons of the glycosphingolipids of normal and transformed cells found differences that prompted speculation that “the structural remodeling of glycolipids and glycoproteins are undoubtedly a key to open a secret box of malignancy” (Hakomori and Murakami,1968). This hypothesis can be reexamined using conventional and “bio-imaging” mass spectrometry, which can be combined with gene expression data for tumors and cancer cell lines to explore the molecular basis for this diversity, and possibly to identify new biomarkers.

The lipid backbones of sphingolipids are additionally interesting because they serve as intracellular and extracellular signals for a wide spectrum of pathways that are important in cancer. This has provided new leads for pharmacologic intervention as well as better understanding of how some chemotherapeutic drugs, and some componsnts of the diet, affect cancer. However, because sphingolipids affect a large number of signaling pathways, it is difficult to interpret and optimize their effects using the typical paradigm of drug discovery (i.e., as agents that are active against a single molecular target). Nonetheless, as an understanding of this complexity has evolved, it has become likely that sphingolipids suppress cancer by modulation of multiple interrelated signaling pathways--in essence, behave like a multi-drug combination. It will probably be necessary to employ the tools of “omics” and systems biology to understand, and capitalize on, the exceptional promise of sphingolipids for cancer detection, chemotherapy and prevention.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED01-02.