Over recent decades, a large body of knowledge has accumulated on the prominent role of lipid deregulation in cancer development. This combined with the powerful drug discovery technologies now available, means that the time is ripe for a lipid-targeted pharmacological approach to cancer. Some important successes have already been achieved. However, there is still the need for a more effective identification of the individual lipid signalling pathways that have a role in tumourigenesis and the connectivities between lipid-based and protein-based transformation processes.
With this in mind, the FEBS Advanced Course on ‘Lipid Signaling and Cancer’, held on 4–10 October 2012 in Vico Equense, Italy, gathered together scientists with relevant expertise in oncology, cell biology and pharmacology. This mix of expertise produced a stimulating and fruitful meeting. The discussion encompassed the relationships between studies of basic cell and molecular processes and more translationally oriented studies on the prevalence of altered lipid metabolism in different cancer types. There was particular focus on those lipid pathways, including phosphoinositides (PIs) and sphingolipids (SLs), where the combination of such studies has led to the identification of small molecules that are able to counteract the transformation process. This series of seven minireviews, written by course participants, highlights both the basic aspects of PI and SL metabolism and their roles in cancer development, as well as their potential as drug targets in cancer treatment.
In the first minireview, Bob Michell illustrates the possible evolutionary origins of the use of inositol in lipids, and challenges the ‘classical’ view of the biosynthetic route to phosphatidylinositol. He then focuses on the important role of phosphatidylinositol 3,5-bisphosphate in the endolysosomal pathway, in the constitutive and stimulated protein trafficking to and from plasma membrane subdomains, and in the control of the TORC1 pathway. Two minireviews discuss the roles of PIs in the nucleus: Nullin Divecha and colleagues report recent progress in the identification of potential polyphosphoinositide-interacting proteins that are involved in transcription, chromatin remodelling and mRNA maturation; and Lucio Cocco and colleagues focus on the nuclear polyphosphoinositide signaling pathway involving nuclear PI-phospholipase C and on the autonomous role that this nuclear PI cycle has in cell cycle progression and differentiation.
The importance of phosphoinositol 3-kinase (PI3K) in autophagy is the focus of the minireview by Harald Stenmark and colleagues, which highlights how the catalytic products of type III and type I PI3Ks [PtdIns3P and PtdIns(3,4,5)P3, respectively] have opposing roles in autophagy and how PI3K-mediated control of autophagy is relevant for understanding tumour suppression and progression.
Three minireviews deal with SL metabolism. Giovanni D'Angelo and colleagues describe the compositional complexity and discuss the potential ‘coding’ role of glycosphingolipids. They also examine current knowledge of glycosphingolipid functions, and approach open questions in the study of the biology of glycosphingolipids. Lina Obeid, Yusuf Hannun and colleagues describe the role of sphingosine-1-phosphate receptor 2 in tumour growth and metastasis and its potential targeting in the treatment of pathologies affecting the immune, nervous, metabolic, cardiovascular, musculoskeletal and renal systems. Finally, Sarah Spiegel and colleagues discuss the role of cholesterol and SL storage in Niemann–Pick type C (NPC) disease, as well as new strategies undertaken to counteract their accumulation in NPC1-null mice. They also report several recent studies suggesting that histone deacetylase inhibitors can correct cholesterol-storage defects in human NPC1 fibroblasts, which may provide promising leads for new therapeutic approaches in the treatment of NPC disease.