Sphingosine 1-phosphate receptors and sphingosine kinase 1: novel biomarkers for clinical prognosis in breast, prostate, and hematological cancers

Abstract

There is substantial evidence for a role in cancer of the bioactive lipid sphingosine 1-phosphate (S1P), the enzyme sphingosine kinase 1 (that catalyses S1P formation) and S1P-specific G protein-coupled receptors. This perspective highlights recent findings demonstrating that sphingosine kinase 1 and S1P receptors are new important biomarkers for detection of early cancer and progression to aggressive cancer. The impact of the sub-cellular distribution of S1P metabolizing enzymes and S1P receptors and their spatial functional interaction with oncogenes is considered with respect to prognostic outcome. These findings suggest that S1P, in addition to being a biomarker of clinical prognosis, might also be a new therapeutic target for intervention in cancer.

Metastatic triple-negative breast cancer is dependent on SphKs/S1P signaling for growth and survival

“…The PI3K/AKT pathways are also involved in crosstalk with RAS/RAF/MEK/ERK and estrogen receptor pathways [45]. As S1P has emerged as a new class of lipid messengers that regulate cell proliferation, differentiation, and migration in vitro [6–8] and also in clinical samples, we became interested to understand whether blocking of both sphingosine kinases inhibited MAPK cascades and PI3K/AKT pathways in metastatic breast cancer LM2-4 cells. In agreement with earlier reports [7,46], extracellular S1P or EGF activates P-ERK, P-p38, P-AKT, and P-p70S6K in MCF-7 cells and inhibiting SphKs activity with DMS [36] attenuated EGF-mediated survival signaling (Fig.…”

“…Finding strategies to cure metastatic TNBC would be beneficial for breast cancer patients. Sphingosine-1-phosphate (S1P) is a potent bioactive lipid mediator produced by the cytosolic SphK1 and the nuclear localized SphK2 from the substrate sphingosine [5], has been known to play important roles to cancer development and progression by regulating tumor proliferation, migration and angiogenesis [6–9]. Although some important roles of intracellular actions of S1P have been discovered [5,10,11], the majority of its biological functions are known to mediated by plasma membrane localized family of five specific G protein coupled receptors (S1PR1-5) [8,12].…”

“…The sphingolipid pathway, particularly SphK signaling, has become of increasing interest as a breast cancer therapeutic target [13,14]. SphK1/S1P, in particular, has been implicated in oncogenic roles in cancer, including proliferation, resistance to apoptosis and tumor growth can be inhibited by SphK1 inhibitors [6,13,15,15,16]. In contrast, specific inhibition of SphK1 with a potent and selective inhibitor PF-543 had no effect on the proliferation and survival of various cancer cells, despite a dramatic change in the intracellular levels of S1P [17,18].…”

Export of sphingosine-1-phosphate and cancer progression

“…Several previous studies demonstrated that cancer cells can secrete S1P ( 54,76,77 ). Moreover, data from preclinical mouse cancer models ( 37,78 ) and human patient samples ( 35,36,79 ) suggest that the tumors themselves with upregulated SphK1 may be a key source of S1P. However, Hla and colleagues ( 51 ) reported that endothelial cells (human umbilical vein vascular endothelial cells and mouse embryonic endothelial cells) synthesize and release endogenous S1P more effi ciently than human colon cancer cell lines.…”

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

“…Therefore, the S1P 4 -HER2 signalling platform enhances signalling gain in response to S1P (Figure 1); this is significant as ERK-1/2 is implicated in promoting metastasis. Indeed, high S1P 4 expression in tumours of ER negative breast cancer patients is also correlated with node positive status, suggesting a role for S1P 4 in metastasis (Ohotoski et al, 2012;Pyne et al, 2012). The link between S1P and metastasis is further evidenced by studies from Ponnusamy et al (2012), who demonstrated a reduction in systemic S1P inhibits TRAMP-induced prostate cancer growth in TRAMP +/+ Sk1 -/-mice or lung metastasis of various cancer cells in Sk1 -/-mice.…”