Expansion of Sphingosine Kinase and Sphingosine-1-Phosphate Receptor Function in Normal and Cancer Cells: From Membrane Restructuring to Mediation of Estrogen Signaling and Stem Cell Programming

Abstract

Sphingolipids, sphingolipid metabolizing enzymes, and their receptors network are being recognized as part of the signaling mechanisms, which govern breast cancer cell growth, migration, and survival during chemotherapy treatment. Approximately 70% of breast cancers are estrogen receptor (ER) positive and, thus, rely on estrogen signaling. Estrogen activates an intracellular network composed of many cytoplasmic and nuclear mediators. Some estrogen effects can be mediated by sphingolipids. Estrogen activates sphingosine kinase 1 (SphK1) and amplifies the intracellular concentration of sphingosine-1-phosphate (S1P) in breast cancer cells during stimulation of proliferation and survival. Specifically, Estrogen activates S1P receptors (S1PR) and induces growth factor receptor transactivation. SphK, S1P, and S1PR expression are causally associated with endocrine resistance and progression to advanced tumor stages in ER-positive breast cancers in vivo. Recently, the network of SphK/S1PR was shown to promote the development of ER-negative cancers and breast cancer stem cells, as well as stimulating angiogenesis. Novel findings confirm and broaden our knowledge about the cross-talk between sphingolipids and estrogen network in normal and malignant cells. Current S1PRs therapeutic inhibition was indicated as a promising chemotherapy approach in non-responsive and advanced malignancies. Considering that sphingolipid signaling has a prominent role in terminally differentiated cells, the impact should be considered when designing specific SphK/S1PR inhibitors. This study analyzes the dynamic of the transformation of sphingolipid axis during a transition from normal to pathological condition on the level of the whole organism. The sphingolipid-based mediation and facilitation of global effects of estrogen were critically accented as a bridging mechanism that should be explored in cancer prevention.

Keywords: breast cancer; cancer stem cells; estrogen receptor; inflammation; sphingolipids; sphingosine kinase; sphingosine-1-phosphate; vasculature.

Figure 1

Normal physiology: the place of sphingolipid signaling pathway. A transverse cut through the artery shows an inside space of the blood vessel filled with blood plasma and blood cells (only erythrocytes are shown), as well as a layer of endothelial cells surrounded by smooth muscle cells. Endothelial cell layer and enlarged single endothelial cell are indicated by a double-ended arrow. Coordinated sphingolipid signaling creates a favorable environment for normal physiological functioning. The activity and expression levels of sphingosine kinases (SphK), sphingosine-1-phosphate (S1P) and its receptors (S1PRs) are maintained at normally low tissue specific levels required for healthy metabolism. Alternatively, high concentration of S1P in blood plasma (and lymph) is supported by release of S1P from endothelial cells, erythrocytes, and platelets. Binding of S1P to S1PRs stimulates activation of an appropriate signaling in cytoplasm and gene activation in nucleus that are followed by quick S1PRs internalization, degradation, and re-cycling. Activation of endogenous SphK by hormones, cytokines, and growth factors results in reduction of sphingosine cell content and production of S1P. S1P/S1PRs axis activates further downstream signaling targets and controls variety of physiological processes including lymphocyte egress from lymphoid organs [5,8,9,14,17,21,62,63,64,65,66,67,68]. Arrows indicate the movement of S1P and direction of its effects (such as activation of S1PR by S1P as ligand, release of S1P by endothelial or cancer cells, etc.). The arrow directed from S1P to the endothelial cell indicates that S1P also activates endothelial cell signaling via S1PRs. Question marks indicate the gaps in our knowledge of SphK/S1P/S1PRs axis.

Figure 2

Cancer scenario: Transformation of SphK/S1P/S1PRs signaling. Cancer cells are shown outside of the artery wall. A transverse cut through the artery shows an inside space of the blood vessel filled with blood plasma and blood cells (only erythrocytes are shown), as well as a layer of endothelial cells surrounded by smooth muscle cells. Endothelial cell layer and enlarged single endothelial cell are indicated by a double-ended arrow. Levels of SphK1 expression and activation are high in cancer cells. The regulation of plasma S1P levels and S1P release by blood cells/endothelial cells remain to be confirmed in cancer patients. S1P levels/S1P gradient is hypothetically changed in blood plasma of cancer patients comparing to healthy controls. It is not clear how changed S1P plasma level would influence the level of S1PR expression and signaling. Overactivation and delayed degradation of S1PRs in cancer cells results in reinforced signaling of this pathway and cancer-related pathological consequences including cancer-directed angiogenesis [21,22,23,70,71,72,73,74,75], formation of tumor microenvironment [32,76,77,78], transformed metabolism [68,79], and cancer progression [5,6,11,67,80,81,82,83]. Arrows indicate the movement of S1P and direction of its effects. The arrow directed from S1P to the endothelial cell indicates that S1P also activates endothelial cell signaling via S1PRs. Question marks indicate the gaps in our knowledge of SphK/S1P/S1PRs axis.

Figure 3

Obesity scenario: transformation and/or adaptation of sphingolipid signaling under condition of metabolic stress (hypothetical scheme). Sphingolipid signaling pathway was proposed to alter during metabolic stress in obese organisms. Blood plasma of obese patients was characterized by dis-regulated S1P gradient, decreased levels of S1P in blood plasma, but higher S1P in specific cells and tissues [102,107,209,210]. Higher S1PR1 and S1PR3 levels were also detected [68]. However, these findings require further confirmation. Black arrows indicate directions of S1P/S1PRs effects. Question marks indicate the gaps in our knowledge of SphK/S1P/S1PRs axis.