Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation

Abstract

Abstract--Sphingosine kinase (there are two isoforms, SK1 and SK2) catalyses the formation of sphingosine 1-phosphate (S1P), a bioactive lipid that can be released from cells to activate a family of G protein-coupled receptors, termed S1P 1-5 . In addition, S1P can bind to intracellular target proteins, such as HDAC1/2, to induce cell responses. There is increasing evidence of a role for S1P receptors (e.g. S1P 4 ) and SK1 in cancer, where high expression of these proteins in ER negative breast cancer patient tumours is linked with poor prognosis.Indeed, evidence will be presented here to demonstrate that S1P 4 is functionally linked with SK1 and the oncogene HER2 (ErbB2) to regulate mitogen-activated protein kinase pathways and growth of breast cancer cells. Although much emphasis is placed on SK1 in terms of involvement in oncogenesis, evidence will also be presented for a role of SK2 in both T-cell and B-cell acute lymphoblastic leukemia. In patient T-ALL lymphoblasts and T-ALL cell lines, we have demonstrated that SK2 inhibitors promote T-ALL cell death via autophagy and induce suppression of c-myc and PI3K/AKT pathways. We will also present evidence demonstrating that certain SK inhibitors promote oxidative stress and protein turnover via proteasomal degradative pathways linked with induction of p53-and p21-induced growth 2 arrest. In addition, the SK1 inhibitor, PF-543 exacerbates disease progression in an experimental autoimmune encephalomyelitis mouse model indicating that SK1 functions in an anti-inflammatory manner. Indeed, sphingosine, which accumulates upon inhibition of SK1 activity, and sphingosine-like compounds promote activation of the inflammasome, which is linked with multiple sclerosis, to stimulate formation of the pro-inflammatory mediator, IL-1β. Such sphingosine like compounds could be exploited to produce antagonists that diminish exaggerated inflammation in disease. The therapeutic potential of modifying the SK-S1P receptor pathway in cancer and inflammation will therefore, be reviewed.3

Recent advances in the development of sphingosine kinase inhibitors

“…Pretreatment with PF-543 also reduced inflammatory responses in a rat model of cerebral ischemia [102] (Table 2). Conversely, PF-543 increased immune infiltration into the spinal cord and increased disease progression in a murine experimental autoimmune encephalomyelitis model of multiple sclerosis [17] (Table 2) suggesting that SK may play a more complex role in the regulation of inflammation in this setting.…”

“…Elevated cellular SK1 and S1P can enhance cell survival, proliferation and migration, [17], promote angiogenesis [18] and contribute to altered cancer cell metabolism [19]. Thus, SK and S1P contribute to many of the hallmarks of cancer [20], and perhaps for this reason, cancer cells often appear to develop a "non-oncogene addiction" to SK1 [21,22].…”

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

“…The focus on bioactive sphingolipid research in signaling mechanisms has expanded from its origin in PKC regulation to multiple biological processes in immunity, inflammation, cellular growth, differentiation, proliferation, apoptosis, metabolism, and related pathologies (Abdel Hadi et al, 2016; Hannun et al, 1986; Hannun and Obeid, 2008; Pyne et al, 2016). Sphingolipids comprise a large class of structural and bioactive lipids that are metabolized in an interconnected network regulated by a large family of enzymes.…”

Vitamin D and Sphingolipids: Role in Bone and Neural System

“…Vitamin D and Sphingolipids: Role in Bone and Neural System http://dx.doi.org/10.5772/66648S1P specific named EDG/S1PR 1-5 have been described to mediate S1P signaling [11,13,14,19]. S1P1, S1P2, and S1P3 show broad tissue gene expression, while S1P4 shows gene expression primarily in immune system cells, and S1P5 is primarily expressed in the spleen (natural killer cells and other lymphocytes) and central nervous system [107].…”