Activation of sphingosine kinase by lipopolysaccharide promotes prostate cancer cell invasion and metastasis via SphK1/S1PR4/matriptase

Lee, Cheng‐Fan; Dang, Andrew; Hernández, Elizabeth; Pong, Rey-Chen; Chen, Benjamin; Sonavane, Rajni; Raj, Ganesh V.; Kapur, Payal; Lin, Hsin-Ying; Wu, Shang-Ru; Ko, Chun-Jung; Lo, U‐Ging; Lee, Hsinyu; Hsieh, Jer‐Tsong; Lee, Ming-Shyue

doi:10.1038/s41388-019-0833-3

Cited by 37 publications

(37 citation statements)

References 76 publications

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“…SphKs exhibit two isoforms, SphK1 and SphK2. SphK1 has emerged as an important and critical signaling enzyme because it involves in many aspects of cancer progression, such as proliferation, angiogenesis, metastasis and chemoresistance [7][8][9]. Consistent with this, we found previously that the expression level of SphK1 was signi cantly increased in EOC tissues and was associated with EOC metastasis and angiogenesis [10,11].…”

Section: Introductionsupporting

confidence: 83%

Inhibition of Sphingosine Kinase 2 Down-Regulates ERK/c-Myc Pathway and Reduces Cell Proliferation in Human Epithelial Ovarian Cancer

Dai

Song

Wang

et al. 2020

Preprint

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Abstract Background: Epithelial ovarian cancer (EOC) is the leading cause of death from female cancers. In our previous study, Sphingosine kinase 2 (SphK2) inhibitor was shown to display anti-EOC activities. The purpose of this study was to further evaluate the expression characteristics and clinical significance of SphK2 in EOC, and to explore the roles and underlying mechanisms of SphK2 in EOC cell survival.Methods: SphK2 expression was examined by Immunohistochemistry and western blot, and its clinical implications and prognostic significance were analyzed. Cellular proliferation assay and mouse xenograft model was established to confirm the roles of SphK2 in vitro and in vivo. Cell cycle analysis, apoptosis assay and western blot were performed to examine cell cycle progression and apoptosis rate. Gene set enrichment analysis (GSEA) and western blot was used to investigate the downstream signaling pathways related to SphK2 function.Results: SphK2 expression level was shown to be associated with stage, histological grade, lymph node metastasis and ascite status. More importantly, high SphK2 expression level was a prognostic indicator of overall survival and relapse-free survival. Moreover, knockdown of SphK2 arrested cell cycle progression and inhibited the proliferation of EOC cells both in vitro and in vivo. Furthermore, ERK/c-Myc, the key pathway in EOC progression, was important for SphK2-mediated mitogenic action in EOC cells.Conclusion: Our findings provided the first evidence that SphK2 played a crucial role in EOC proliferation by regulating ERK/c-Myc pathway. SphK2 may serve as a prognostic marker and potential therapeutic target in EOC.

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Section: Introductionsupporting

confidence: 83%

Inhibition of Sphingosine Kinase 2 Down-Regulates ERK/c-Myc Pathway and Reduces Cell Proliferation in Human Epithelial Ovarian Cancer

Dai

Song

Wang

et al. 2020

Preprint

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“…Among the key players of the sphingolipid metabolic pathway, much attention has been paid to SphKs because their catalytic activity lies at the critical juncture in regulating sphingolipid metabolism. The SphKs exhibit 2 isoforms, SphK1 and SphK2, of which SphK1 has emerged as an important and critical signaling enzyme because it is involved in many aspects of cancer progression, such as proliferation, angiogenesis, metastasis, and chemoresistance (9)(10)(11). Consistent with this, we found previously that the expression level of SphK1 was significantly increased in EOC tissues and was associated with EOC metastasis and angiogenesis (12,13).…”

Section: Introductionsupporting

confidence: 74%

Inhibition of sphingosine kinase 2 down-regulates ERK/c-Myc pathway and reduces cell proliferation in human epithelial ovarian cancer

Dai¹,

Wang²,

Liu³

et al. 2021

Ann Transl Med

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Background: Epithelial ovarian cancer (EOC) is the leading cause of death from female cancers. In our previous study, sphingosine kinase 2 (SphK2) inhibitor was shown to display anti-EOC activities. The purpose of this study was to evaluate further the expression characteristics and clinical significance of SphK2 in EOC and to explore the roles and underlying mechanisms of SphK2 in EOC cell survival.Methods: The expression of SphK2 was examined by immunohistochemistry (IHC) and Western blot, and its clinical implications and prognostic significance were analyzed. We performed a cellular proliferation assay, and a mouse xenograft model was established to confirm the roles of SphK2 in vitro and in vivo.Cell cycle analysis, apoptosis assay, and Western blot were performed to examine cell cycle progression and apoptosis rate. Gene set enrichment analysis (GSEA), and Western blot were used to investigate the downstream signaling pathways related to SphK2 function.Results: The expression level of SphK2 was shown to be associated with stage, histological grade, lymph node metastasis, and ascites status. More importantly, a high SphK2 expression level was a prognostic indicator of overall survival (OS) and relapse-free survival (RFS). Moreover, knockdown of SphK2 arrested cell cycle progression and inhibited EOC cell proliferation both in vitro and in vivo. Furthermore, ERK/ c-Myc, the key pathway in EOC progression, was important for SphK2-mediated mitogenic action in EOC cells.Conclusions: Our findings provided the first evidence that SphK2 played a crucial role in EOC proliferation by regulating the ERK/c-Myc pathway. This indicated that SphK2 might serve as a prognostic marker and potential therapeutic target in EOC.

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“…Activation of Toll-like receptor 4 (TLR4) by LPS promotes Ser225 phosphorylation of SK1, resulting in its translocation from the cytoplasm to the plasma membrane, release of S1P and S1P 4 -induced activation of matriptase. A similar phenomenon occurs in tumour explants from prostate cancer patients where poor survival is correlated with increased SK1 expression and tumour Gleason grade [58]. However, S1P 2 agonists might be useful in the management of chemotherapy-induced neuropathy since the selective S1P 2 agonist, CYM-5478, reduces allodynia in cisplatin-induced neuropathy and attenuates the associated inflammatory processes in the dorsal root ganglia via the transcription factor ATF3 and haeme oxygenase 1 (HO-1) [59].…”

Section: Role Of S1p In Tumour Neovascularisation and Metastasismentioning

confidence: 75%

Recent advances in the role of sphingosine 1‐phosphate in cancer

Pyne

2020

FEBS Letters

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Sphingosine 1-phosphate (S1P) is a bioactive lipid that binds to a family of G protein-coupled receptors (S1P 1-5) and intracellular targets, such as HDAC1/ 2, that are functional in normal and pathophysiologic cell biology. There is a significant role for sphingosine 1-phosphate in cancer underpinning the socalled hallmarks, such as transformation and replicative immortality. In this review, we survey the most recent developments concerning the role of sphingosine 1-phosphate receptors, sphingosine kinase and S1P lyase in cancer and the prognostic indications of these receptors and enzymes in terms of diseasespecific survival and recurrence. We also provide evidence for identification of new therapeutic approaches targeting sphingosine 1-phosphate to prevent neovascularisation, to revert aggressive and drug-resistant cancers to more amenable forms sensitive to chemotherapy, and to induce cytotoxicity in cancer cells. Finally, we briefly describe current advances in the development of isoform-specific inhibitors of sphingosine kinases for potential use in the treatment of various cancers, where these enzymes have a predominant role. This review will therefore highlight sphingosine 1-phosphate signalling as a promising translational target for precision medicine in stratified cancer patients.

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Activation of sphingosine kinase by lipopolysaccharide promotes prostate cancer cell invasion and metastasis via SphK1/S1PR4/matriptase

Cited by 37 publications

References 76 publications

Inhibition of Sphingosine Kinase 2 Down-Regulates ERK/c-Myc Pathway and Reduces Cell Proliferation in Human Epithelial Ovarian Cancer

Inhibition of Sphingosine Kinase 2 Down-Regulates ERK/c-Myc Pathway and Reduces Cell Proliferation in Human Epithelial Ovarian Cancer

Inhibition of sphingosine kinase 2 down-regulates ERK/c-Myc pathway and reduces cell proliferation in human epithelial ovarian cancer

Recent advances in the role of sphingosine 1‐phosphate in cancer

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