Sphingosine-1-phosphate and estrogen signaling in breast cancer

Maczis, Melissa A.; Milstien, Sheldon; Spiegel, Sarah

doi:10.1016/j.jbior.2015.09.006

Cited by 40 publications

(39 citation statements)

References 46 publications

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“…As key players in normal physiology and in disease, it is unsurprising that there is a large body of evidence demonstrating the contribution of an imbalance in the SphK/S1P rheostat to a plethora of pathological conditions including cancer, diabetes, inflammatory diseases, neurodegenerative diseases (Parkinson's and Alzheimer's), cardiovascular and liver diseases, which have been extensively reviewed [2, 3, 11, 15, 18, 48, 56–72]. Although removal of one of the major SphK isozymes is not fatal, as determined in mice with knockout of either SphK1 or SphK2, what these studies have revealed is that loss of one isozyme increases the risk of major health problems including altered vasculature formation [73, 74], impairment in wound healing [75], abnormal islet formation, which could lead to type 1 diabetes [76], and cardiac dysfunction (ischemic) [77], among other complications.…”

Section: Involvement Of Sphk and S1p In The Pathogenesis Of Cancer Anmentioning

confidence: 99%

“…Since SphKs have been recognized as major driver proteins in many cancer types, there has been much interest in targeting the overexpression of human SphK1 (hSphK1)/S1P as an anticancer treatment [11, 15, 27, 48, 57, 60, 239, 269–276]. However, the design of drugs to inhibit SphK/S1P action has inherent complexities due to the diversity of SphK functions and its important role(s) in normal physiology.…”

Section: Sphk/s1p Designer Drugsmentioning

confidence: 99%

“…Prime examples include breast, cervical, prostate, head and neck, and brain cancers. Overexpression of SphK1 and differential S1PRs distribution are associated with poor prognosis and disease stage in breast cancer and may prove to be strong candidates as diagnostic and prognositic markers for ER+ and ER- breast cancers, endocrine resistance, and metastasis [11, 230, 340]. In cervical cancer SphK1 was significantly increased in comparison to normal tissues and patients had a higher probability of recurrence and lower overall survival [130].…”

Section: Sphk/s1prs As Diagnostic or Therapeutic Molecular Biomarkersmentioning

confidence: 99%

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Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget

et al. 2017

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The various sphingosine kinase (SphK) isoenzymes (isozymes) and isoforms, key players in normal cellular physiology, are strongly implicated in cancer and other diseases. Mutations in SphKs, that may justify abnormal physiological function, have not been recorded. Nonetheless, there is a large and growing body of evidence demonstrating the contribution of gain or loss of function and the imbalance in the SphK/S1P rheostat to a plethora of pathological conditions including cancer, diabetes and inflammatory diseases. SphK is expressed as two isozymes SphK1 and SphK2, transcribed from genes located on different chromosomes and both isozymes catalyze the phosphorylation of sphingosine to S1P. Expression of each SphK isozyme produces alternately spliced isoforms. In recent years the importance of the contribution of SpK1 expression to treatment resistance in cancer has been highlighted and, additionally, differences in treatment outcome appear to also be dependent upon SphK isoform expression. This review focuses on an exciting emerging area of research involving SphKs functions, expression and subcellular localization, highlighting the complexity of targeting SphK in cancer and also comorbid diseases. This review also covers the SphK isoenzymes and isoforms from a historical perspective, from their first discovery in murine species and then in humans, their role(s) in normal cellular function and in disease processes, to advancement of SphK as an oncotarget.

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Section: Involvement Of Sphk and S1p In The Pathogenesis Of Cancer Anmentioning

confidence: 99%

Section: Sphk/s1p Designer Drugsmentioning

confidence: 99%

Section: Sphk/s1prs As Diagnostic or Therapeutic Molecular Biomarkersmentioning

confidence: 99%

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Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget

et al. 2017

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“…Circulating S1P in humans is associated with a negative effect on bone mass, although S1P in osteoblasts promotes growth and survival . Estrogen modulates S1P production in cells including astroglia, breast, and endothelium . In bone, estrogen is essential for skeletal development and maintenance with a mixture of direct and indirect effects on growth and on the balance of bone formation and resorption .…”

Section: Introductionmentioning

confidence: 99%

Sphingosine‐1‐Phosphate Modulates the Effect of Estrogen in Human Osteoblasts

et al. 2018

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Production of sphingosine-1-phosphate (S1P) is linked to 17β-estradiol (E2) activity in many estrogen-responsive cells; in bone development, the role of S1P is unclear. We studied effects of S1P on proliferation and differentiation of human osteoblasts (hOB). Ten nM E2, 1 μM S1P, or 1 μM of the S1P receptor 1 (S1PR1) agonist SEW2871 increased hOB proliferation at 24 hours. S1PR 1, 2, and 3 mRNAs are expressed by hOB but not S1PR4 or S1PR5. Expression of S1PR2 was increased at 7 and 14 days of differentiation, in correspondence with osteoblast-related mRNAs. Expression of S1PR1 was increased by E2 or S1P in proliferating hOB, whereas S1PR2 mRNA was unaffected in proliferating cells; S1PR3 was not affected by E2 or S1P. Inhibiting sphingosine kinase (SPHK) activity with sphingosine kinase inhibitor (Ski) greatly reduced the E2 proliferative effect. Both E2 and S1P increased SPHK mRNA at 24 hours in hOB. S1P promoted osteoblast proliferation via activating MAP kinase activity. Either E2 or S1P increased S1P synthesis in a fluorescent S1P assay. Interaction of E2 and S1P signaling was indicated by upregulation of E2 receptor mRNA after S1P treatment. E2 and S1P also promoted alkaline phosphatase expression. During osteoblast differentiation, S1P increased bone-specific mRNAs, similarly to the effects of E2. However, E2 and S1P showed differences in the activation of some osteoblast pathways. Pathway analysis by gene expression arrays was consistent with regulation of pathways of osteoblast differentiation; collagen and cell adhesion proteins centered on Rho/Rac small GTPase signaling and Map kinase or signal transducer and activator of transcription (Stat) intermediates. Transcriptional activation also included significant increases in superoxide dismutase 1 and 2 transcription by either S1P or E2. We demonstrate that the SPHK system is a co-mediator for osteoblast proliferation and differentiation, which is mainly, but not entirely, complementary to E2, whose effects are mediated by S1PR1 and S1PR2.

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“…In the last decade, sphingolipid mediators including sphingosine, ceramide and sphingosine-1-phosphate (S1P), S1P receptors (S1PRs), and enzymes of S1P metabolism, have been identified as key modulators of several human pathologies including pulmonary diseases (Natarajan et al, 2013; Ebenezer et al, 2016a), cancers (Pyne and Pyne, 2010; Pyne et al, 2014) including breast cancer (Macziz et al, 2016) and immune responses (Spiegel and Milstien, 2011; Hisano et al, 2012). Among the sphingolipid metabolites, S1P has been shown to have both beneficial and detrimental effect on lung inflammation and vascular integrity.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase

Ebenezer

Suryadevara

et al. 2017

Advances in Biological Regulation

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Cellular level of sphingosine-1-phosphate (S1P), the simplest bioactive sphingolipid, is tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and degradation mediated by S1P phosphatases, lipid phosphate phosphatases, and S1P lyase. The pleotropic actions of S1P are attributed to its unique inside-out (extracellular) signaling via G-protein-coupled S1P1-5 receptors, and intracellular receptor independent signaling. Additionally, S1P generated in the nucleus by nuclear SphK2 modulates HDAC1/2 activity, regulates histone acetylation, and transcription of pro-inflammatory genes. Here, we present data on the role of S1P lyase mediated S1P signaling in regulating LPS-induced inflammation in lung endothelium. Blocking S1P lyase expression or activity attenuated LPS-induced histone acetylation and secretion of pro-inflammatory cytokines. Degradation of S1P by S1P lyase generates Δ2-hexadecenal and ethanolamine phosphate and the long-chain fatty aldehyde produced in the cytoplasmic compartment of the endothelial cell seems to modulate histone acetylation pattern, which is different from the nuclear SphK2/S1P signaling and inhibition of HDAC1/2. These in vitro studies suggest that S1P derived long-chain fatty aldehyde may be an epigenetic regulator of pro-inflammatory genes in sepsis-induced lung inflammation. Trapping fatty aldehydes and other short chain aldehydes such as 4-hydroxynonenal derived from S1P degradation and lipid peroxidation, respectively by cell permeable agents such as phloretin or other aldehyde trapping agents may be useful in treating sepsis-induced lung inflammation via modulation of histone acetylation.

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Sphingosine-1-phosphate and estrogen signaling in breast cancer

Cited by 40 publications

References 46 publications

Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget

Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget

Sphingosine‐1‐Phosphate Modulates the Effect of Estrogen in Human Osteoblasts

Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase

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