S1P is a small bioactive lipid which exerts its effects following binding to a family of five G protein-coupled receptors, known as S1P1-5. Following receptor activation, multiple signalling cascades are activated, allowing S1P to regulate a range of cellular processes, such as proliferation, apoptosis, migration and angiogenesis. There is strong evidence implicating the involvement of S1P receptors (S1PRs) in cancer progression and the oncogenic effects of S1P can result from alterations in the expression of one or more of the S1PRs and/or the enzymes that regulate the levels of S1P. However, cooperativity between the individual S1PRs, functional interactions with receptor tyrosine kinases and the sub-cellular localisation of the S1PRs within tumour cells also appear to play a role in mediating the effects of S1PR signalling during carcinogenesis. Here we review what is known regarding the role of individual S1PRs in cancer and discuss the recent evidence to suggest cross-talk between the S1PRs and other cellular signalling pathways in cancer. We will also discuss the therapeutic potential of targeting the S1PRs and their downstream signalling pathways for the treatment of cancer.
Cancer stem cells (CSCs) represent rare tumor cell populations capable of self-renewal, differentiation, and tumor initiation and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches that can effectively target CSCs and tumor cells could be the key to efficient tumor treatment. In this study, we explored the function of SPHK1 in breast CSCs and non-CSCs. We showed that RNAi-mediated knockdown of SPHK1 inhibited cell proliferation and induced apoptosis in both breast CSCs and non-CSCs, while ectopic expression of SPHK1 enhanced breast CSC survival and mammosphere forming efficiency. We identified STAT1 and IFN signaling as key regulatory targets of SPHK1 and demonstrated that an important mechanism by which SPHK1 promotes cancer cell survival is through the suppression of STAT1. We further demonstrated that SPHK1 inhibitors, FTY720 and PF543, synergized with doxorubicin in targeting both breast CSCs and non-CSCs. In conclusion, we provide important evidence that SPHK1 is a key regulator of cell survival and proliferation in breast CSCs and non-CSCs and is an attractive target for the design of future therapies.
Lipopolysaccharide is an endotoxin to induce sickness behavior in several animal models to explore the link between immune activation and cognition. Neuroinflammation playing a pivotal role in disease progress is evidently influenced by sphingosine-1-phosphate. As one of the sphingosine analogs in clinical use for multiple sclerosis, fingolimod (FTY720) was shown to substantially affect gene expression profile in the context of AD in our previous experiments. The present study was designed to evaluate the drug efficacy in the context of the mere inflammatory context leading to memory impairment. FTY720 was repeatedly administered for a few days before or after intracerebral lipopolysaccharide (LPS) injection in rats. Animal's brains were then assigned to histological as well as multiplex mRNA assay following memory performance test. Both FTY720 pre-treatment and post-treatment were similarly capable of ameliorating LPS-induced memory impairment as assessed by passive avoidance test. Such amending effects may be partly accountable by the concomitant alterations in transcriptional levels of mitogen-activated protein kinases as well as inflammatory genes determined by QuantiGene Plex analysis. These findings confirming FTY720 application benefits suggest its efficacy may not differ significantly while considered either as a preventive or as a therapeutic approach against neuroinflammation.
Alzheimer's disease (AD) as a neurodegenerative brain disorder is the most common cause of dementia. To date, there is no causative treatment for AD and there are few preventive treatments either. The sphingosine-1-phosphate receptor modulator FTY720 (fingolimod) prevents lymphocytes from contributing to an autoimmune reaction and has been approved for multiple sclerosis treatment. In concert with other studies showing the anti-inflammatory and protective effect of FTY720 in some neurodegenerative disorders like ischemia, we have recently shown that FTY720 chronic administration prevents from impairment of spatial learning and memory in AD rats. Here FTY720 was examined on AD rats in comparison to the only clinically approved NMDA receptor antagonist, Memantine. Passive avoidance task showed significant memory restoration in AD animals received FTY720 comparable to Memantine. Upon gene profiling by QuantiGene Plex, this behavioral outcomes was concurrent with considerable alterations in some genes transcripts like that of mitogen activated protein kinases (MAPKs) and some inflammatory markers that may particularly account for the detected decline in hippocampal neural damage or memory impairment associated with AD. From a therapeutic standpoint, our findings conclude that FTY720 may suggest new opportunities for AD management probably based on several modulatory effects on genes involved in cell death or survival.