Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer

German Research FoundationWilhelm Sander-StiftungNational Health and Medical Research Council of AustraliaCancer Council QueenslandMovember FoundationProstate Cancer Foundation of Australia through a Movember Revolutionary Team AwardQueensland University of TechnologyGerman Academic Exchange Service (German-Australian Network for Personalized Medicine

Aberrant expression of the S1P regulating enzymes, SPHK1 and SGPL1, contributes to a migratory phenotype in OSCC mediated through S1PR2.

Oral squamous cell carcinoma (OSCC) is a lethal disease with a 5-year mortality rate of around 50%. Molecular targeted therapies are not in routine use and novel therapeutic targets are required. Our previous microarray data indicated sphingosine 1-phosphate (S1P) metabolism and signalling was deregulated in OSCC. In this study, we have investigated the contribution of S1P signalling to the pathogenesis of OSCC. We show that the expression of the two major enzymes that regulate S1P levels were altered in OSCC: SPHK1 was significantly upregulated in OSCC tissues compared to normal oral mucosa and low levels of SGPL1 mRNA correlated with a worse overall survival. In in vitro studies, S1P enhanced the migration/invasion of OSCC cells and attenuated cisplatin-induced death. We also demonstrate that S1P receptor expression is deregulated in primary OSCCs and that S1PR2 is over-expressed in a subset of tumours, which in part mediates S1P-induced migration of OSCC cells. Lastly, we demonstrate that FTY720 induced significantly more apoptosis in OSCC cells compared to non-malignant cells and that FTY720 acted synergistically with cisplatin to induce cell death. Taken together, our data show that S1P signalling promotes tumour aggressiveness in OSCC and identify S1P signalling as a potential therapeutic target.This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text via the publisher's site.Published (Open Access

Role of Bioactive Sphingolipids in Inflammation and Eye Diseases

Inflammation is a common underlying factor in a diversity of ocular diseases, ranging from macular degeneration, autoimmune uveitis, glaucoma, diabetic retinopathy and microbial infection. In addition to the variety of known cellular mediators of inflammation, such as cytokines, chemokines and lipid mediators, there is now considerable evidence that sphingolipid metabolites also play a central role in the regulation of inflammatory pathways. Various sphingolipid metabolites, such as ceramide (Cer), ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P), and lactosylceramide (LacCer) can contribute to ocular inflammatory diseases through multiple pathways. For example, inflammation generates Cer from sphingomyelins (SM) in the plasma membrane, which induces death receptor ligand formation and leads to apoptosis of retinal pigment epithelial (RPE) and photoreceptor cells. Inflammatory stress by reactive oxygen species leads to LacCer accumulation and S1P secretion and induces proliferation of retinal endothelial cells and eventual formation of new vessels. In sphingolipid/lysosomal storage disorders, sphingolipid metabolites accumulate in lysosomes and can cause ocular disorders that have an inflammatory etiology. Sphingolipid metabolites activate complement factors in the immune-response mediated pathogenesis of macular degeneration. These examples highlight the integral association between sphingolipids and inflammation in ocular diseases