Sphingosine kinase 1 overexpression is associated with poor prognosis and oxaliplatin resistance in hepatocellular carcinoma

Wang, Fangping; Wu, Zhiming

doi:10.3892/etm.2018.6086

Cited by 22 publications

(28 citation statements)

References 25 publications

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“…High levels of SPHK1 were shown to enhance tumor formation in breast cancer MCF-7 cells 43 . Overexpression of SPHK1 enzyme has also been reported in hepatocellular carcinoma and adrenocortical carcinoma tissues 44,45 . The S1P/SPHK1 axis has also been reported earlier to promote the pancreatic cancer growth by regulating the expression of pancreatic stellate cells 46 .…”

Section: Discussionmentioning

confidence: 94%

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

Bhadwal¹,

Dahiya²,

Shinde³

et al. 2020

Sci Rep

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perturbations in lipid metabolic pathways to meet the bioenergetic and biosynthetic requirements is a principal characteristic of cancer cells. Sphingolipids (SpLs) are the largest class of bioactive lipids associated to various aspects of tumorigenesis and have been extensively studied in cancer cell lines and experimental models. the clinical relevance of SpLs in human malignancies however is still poorly understood and needs further investigation. in the present study, we adopted a UHpLc-High resolution (orbitrap) Mass spectrometry (HRMS) approach to identify various sphingolipid species in breast cancer patients. A total of 49 SPLs falling into 6 subcategories have been identified. Further, integrating the multivariate analysis with metabolomics enabled us to identify an elevation in the levels of ceramide phosphates and sphingosine phosphates in tumor tissues as compared to adjacent normal tissues. the expression of genes involved in the synthesis of reported metabolites was also determined in local as well as TCGA cohort. A significant upregulation in the expression of CERK and SPHK1 was observed in tumor tissues in local and tcGA cohort. Sphingomyelin levels were found to be high in adjacent normal tissues. Consistent with the above findings, expression of SGMS1 in tumor tissues was downregulated in tcGA cohort only. clinical correlations of the selected metabolites and their performance as biomarkers was also evaluated. Significant ROC and positive correlation with Ki67 index highlight the diagnostic potential and clinical relevance of ceramide phosphates in breast cancer.Dysregulation of lipid homeostasis has become an established hallmark of cancer. The cancer cells exploit lipid metabolic pathways in order to fulfil their demand for energy as well as biosynthetic precursors. Aberrations in lipid metabolism thus affects numerous cellular processes such as cell growth, proliferation, differentiation and cell survival 1 . Sphingolipids (SPLs), apart from the inceptive view of being considered as mere structural components, have evolved as crucial regulators of myriads of cellular functions. The primary elements of sphingolipid metabolism such as ceramide, ceramide 1-phosphate and sphingosine 1-phosphate have recently emerged as key regulators in cancer cell growth, proliferation, survival, migration and drug resistance 2-4 . Numerous studies have described the elementary role of ceramide and sphingosine 1-phosphate rheostat in various types of cancers such as lung, breast and colon. However, these studies have provided the mechanistic details of sphingolipid metabolism in cancer cell lines and experimental models 5-7 , while their role in human malignancies is still poorly understood and needs further elucidation.Breast cancer continues to remain the most common malignancy among women worldwide 8 . The diagnosis rate of breast cancer among Indian females is as high as 25.8 per 100,000 women with a mortality rate of 12.7 per 100,000 women 9 . Despite advancement in diagnostic and therapeutic modalities, th...

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Section: Discussionmentioning

confidence: 94%

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

Bhadwal¹,

Dahiya²,

Shinde³

et al. 2020

Sci Rep

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“…In 2006, Bonhoure et al ( 25 ) reported that SphK1 contributes to MDR-associated chemoresistance in acute myeloid leukemia. The role of SphK1 in chemoresistance has also been investigated in several different types of cancer, including breast ( 26 ), colon ( 27 ) and gastroesophageal cancer ( 28 ), as well as hepatocellular carcinoma ( 12 ). A study conducted by Wang and Wu ( 12 ) reported that SphK1 expression was associated with poor prognosis and oxaliplatin resistance in hepatocellular carcinoma ( 12 ).…”

Section: Discussionmentioning

confidence: 99%

Sphingosine kinase 1 contributes to doxorubicin resistance and glycolysis in osteosarcoma

Ren

2020

Mol Med Rep

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Osteosarcoma (OS) is one of the most common and aggressive malignancies in children and adolescents worldwide. Sphingosine kinase 1 (SphK1) has recently been reported to serve a role in OS progression. The present study aimed to investigate the role of SphK1 in the development of chemoresistance and glycolysis in OS cell lines. SphK1 expression levels in OS cell lines (U2OS, MG63 and SaoS2) were analyzed using western blotting and reverse transcription-quantitative PCR (RT-qPCR). A cell survival assay was conducted to determine doxorubicin-resistance in OS cells, and glycolysis was also evaluated. SphK1 expression was increased in the U2OS and SaoS2 cell lines, and both cell lines were more resistant to doxorubicin when compared with the MG63 cell line. SphK1 knockdown or overexpression altered doxorubicin resistance and the viability of OS cell lines. In addition, hypoxia inducible factor-1α (HIF-1α) expression was positively associated with SphK1 expression, and partly mediated SphK1-induced effects on doxorubicin resistance and glycolysis. The present study suggested that SphK1 participated in the development of doxorubicin resistance and contributed to glycolysis in OS cells by regulating HIF-1α expression. However, further studies investigating the application of SphK1 associated therapies for patients with OS are required.

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“…To date, SphK1 and SphK2 have been identified as the two isoforms of SphKs. Considerable attention has been devoted to the involvement of SphK1 in multiple cancers including HCC (10). Recently, the other isoform of SphK, SphK2, also received increasing attention and may be an important regulator of cancer development and progression (11).…”

Section: Introductionmentioning

confidence: 99%

Targeting SphK2 Reverses Acquired Resistance of Regorafenib in Hepatocellular Carcinoma

Shi

Zhang

et al. 2020

Front. Oncol.

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Background: Regorafenib is a second-line therapy drug used for advanced hepatocellular carcinoma (HCC). Unfortunately, the survival benefit of the patients receiving this treatment is modest, which may be attributed to drug resistance. In the present study, sphingosine kinase 2 (SphK2) was targeted to reverse regorafenib resistance in HCC. Methods: The functions of SphK2 and sphingosine-1-phosphate (S1P), the catalytic product of SphK2 in regorafenib resistance of HCC cells, were evaluated by cell counting kit-8 assay, colony formation, cell cycle evaluation, and annexin V-fluorescein isothiocyanate/propidium iodide double-staining assay. The antitumor activity of combined treatment of regorafenib and the SphK2-specific inhibitor ABC294640 was examined in HCC cells in vitro and xenograft model in vivo. The molecular mechanisms of SphK2/S1P-mediating regorafenib resistance were investigated using cell line establishment and Western blot analysis. Results: Well-developed regorafenib-resistant HCC cells indicated high expression levels of SphK2. The sensitivity to regorafenib of regorafenib-resistant HCC cells was restored following SphK2 knockdown or pharmacological inhibition by ABC294640. In addition, ectopic expression of SphK2 and exogenous addition of S1P decreased the sensitivity of HCC cells to regorafenib. Furthermore, the combination treatment with ABC294640 sensitized resistant tumor to regorafenib in xenograft model of HCC. The phosphorylation levels of nuclear factor κB (NF-κB), as well as those of signal transducer and activator of transcription 3 (STAT3), were positively associated with SphK2 and S1P. Conclusions: SphK2/S1P mediates regorafenib resistance of HCC through NF-κB and STAT3 activation. Targeting SphK2 by ABC294640 potently reduces regorafenib resistance of HCC cells both in vitro and in vivo. The combination of ABC294640 and regorafenib could be developed as a novel potential treatment strategy for advanced HCC.

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Sphingosine kinase 1 overexpression is associated with poor prognosis and oxaliplatin resistance in hepatocellular carcinoma

Cited by 22 publications

References 25 publications

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

Sphingosine kinase 1 contributes to doxorubicin resistance and glycolysis in osteosarcoma

Targeting SphK2 Reverses Acquired Resistance of Regorafenib in Hepatocellular Carcinoma

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