Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer

Kasia Matula, Elaina Collie-Duguid, Graeme Murray, Khyati Parikh, Heike Grabsch, Patrick Tan, Salina Lalwani, Roberta Garau, Yuhan Ong, Gillian Bain, Asa-Dahle Smith, Gordon Urquhart, Jacek Bielawski, Michael Finnegan, Russell Petty

    Research output: Contribution to journalArticle

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    Abstract

    BACKGROUND: Resistance to chemotherapy is common in gastroesophageal cancer. Mechanisms of resistance are incompletely characterised and there are no predictive biomarkers in clinical practice for cytotoxic drugs. We used new cell line models to characterise novel chemotherapy resistance mechanisms and validated them in tumour specimens to identify new targets and biomarkers for gastroesophageal cancer.

    METHODS: Cell lines were selected for resistance to oxaliplatin, cisplatin and docetaxel and gene expression examined using Affymetrix Exon 1.0 ST arrays. Leads were validated by qRT-PCR and HPLC of tumour metabolites. Protein expression and pharmacological inhibition of lead target SPHK1 was evaluated in independent cell lines, and by immunohistochemistry in gastroesophageal cancer patients.

    RESULTS: Genes with differential expression in drug resistant cell lines compared to the parental cell line they were derived from, were identified for each drug resistant cell line. Biological pathway analysis of these gene lists, identified over-represented pathways, and only 3 pathways - lysosome, sphingolipid metabolism and p53 signalling- were identified as over-represented in these lists for all three cytotoxic drugs investigated. The majority of genes differentially expressed in chemoresistant cell lines from these pathways, were involved in metabolism of glycosphingolipids and sphingolipids in lysosomal compartments suggesting that sphingolipids might be important mediators of cytotoxic drug resistance in gastroeosphageal cancers . On further investigation, we found that drug resistance (IC50) was correlated with increased sphingosine kinase 1(SPHK1) mRNA and also with decreased sphingosine-1-phosphate lysase 1(SGPL1) mRNA. SPHK1 and SGPL1 gene expression were inversely correlated. SPHK1:SGPL1 ratio correlated with increased cellular sphingosine-1-phosphate (S1P), and S1P correlated with drug resistance (IC50). High SPHK1 protein correlated with resistance to cisplatin (IC50) in an independent gastric cancer cell line panel and with survival of patients treated with chemotherapy prior to surgery but not in patients treated with surgery alone. Safingol a SPHK1 inhibitor, was cytotoxic as a single agent and acted synergistically with cisplatin in gastric cancer cell lines.

    CONCLUSION: Agents that inhibit SPHK1 or S1P could overcome cytotoxic drug resistance in gastroesophageal cancer. There are several agents in early phase human trials including Safingol that could be combined with chemotherapy or used in patients progressing after chemotherapy.

    Original languageEnglish
    Article number762
    Number of pages14
    JournalBMC Cancer
    Volume15
    Issue number1
    DOIs
    Publication statusPublished - 22 Oct 2015

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    Sphingosine
    Lyases
    Drug Therapy
    Cell Line
    Drug Resistance
    Neoplasms
    Sphingolipids
    Cisplatin
    Inhibitory Concentration 50
    oxaliplatin
    docetaxel
    Pharmaceutical Preparations
    Stomach Neoplasms
    Genes
    Gene Expression
    sphingosine kinase
    sphingosine 1-phosphate
    Glycosphingolipids
    Messenger RNA
    Tumor Biomarkers

    Cite this

    Matula, Kasia ; Collie-Duguid, Elaina ; Murray, Graeme ; Parikh, Khyati ; Grabsch, Heike ; Tan, Patrick ; Lalwani, Salina ; Garau, Roberta ; Ong, Yuhan ; Bain, Gillian ; Smith, Asa-Dahle ; Urquhart, Gordon ; Bielawski, Jacek ; Finnegan, Michael ; Petty, Russell. / Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer. In: BMC Cancer. 2015 ; Vol. 15, No. 1.
    @article{0c6d04d0a4014eb78359f4307f0ecdb1,
    title = "Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer",
    abstract = "BACKGROUND: Resistance to chemotherapy is common in gastroesophageal cancer. Mechanisms of resistance are incompletely characterised and there are no predictive biomarkers in clinical practice for cytotoxic drugs. We used new cell line models to characterise novel chemotherapy resistance mechanisms and validated them in tumour specimens to identify new targets and biomarkers for gastroesophageal cancer.METHODS: Cell lines were selected for resistance to oxaliplatin, cisplatin and docetaxel and gene expression examined using Affymetrix Exon 1.0 ST arrays. Leads were validated by qRT-PCR and HPLC of tumour metabolites. Protein expression and pharmacological inhibition of lead target SPHK1 was evaluated in independent cell lines, and by immunohistochemistry in gastroesophageal cancer patients.RESULTS: Genes with differential expression in drug resistant cell lines compared to the parental cell line they were derived from, were identified for each drug resistant cell line. Biological pathway analysis of these gene lists, identified over-represented pathways, and only 3 pathways - lysosome, sphingolipid metabolism and p53 signalling- were identified as over-represented in these lists for all three cytotoxic drugs investigated. The majority of genes differentially expressed in chemoresistant cell lines from these pathways, were involved in metabolism of glycosphingolipids and sphingolipids in lysosomal compartments suggesting that sphingolipids might be important mediators of cytotoxic drug resistance in gastroeosphageal cancers . On further investigation, we found that drug resistance (IC50) was correlated with increased sphingosine kinase 1(SPHK1) mRNA and also with decreased sphingosine-1-phosphate lysase 1(SGPL1) mRNA. SPHK1 and SGPL1 gene expression were inversely correlated. SPHK1:SGPL1 ratio correlated with increased cellular sphingosine-1-phosphate (S1P), and S1P correlated with drug resistance (IC50). High SPHK1 protein correlated with resistance to cisplatin (IC50) in an independent gastric cancer cell line panel and with survival of patients treated with chemotherapy prior to surgery but not in patients treated with surgery alone. Safingol a SPHK1 inhibitor, was cytotoxic as a single agent and acted synergistically with cisplatin in gastric cancer cell lines.CONCLUSION: Agents that inhibit SPHK1 or S1P could overcome cytotoxic drug resistance in gastroesophageal cancer. There are several agents in early phase human trials including Safingol that could be combined with chemotherapy or used in patients progressing after chemotherapy.",
    author = "Kasia Matula and Elaina Collie-Duguid and Graeme Murray and Khyati Parikh and Heike Grabsch and Patrick Tan and Salina Lalwani and Roberta Garau and Yuhan Ong and Gillian Bain and Asa-Dahle Smith and Gordon Urquhart and Jacek Bielawski and Michael Finnegan and Russell Petty",
    year = "2015",
    month = "10",
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    doi = "10.1186/s12885-015-1718-7",
    language = "English",
    volume = "15",
    journal = "BMC Cancer",
    issn = "1471-2407",
    publisher = "Springer Verlag",
    number = "1",

    }

    Matula, K, Collie-Duguid, E, Murray, G, Parikh, K, Grabsch, H, Tan, P, Lalwani, S, Garau, R, Ong, Y, Bain, G, Smith, A-D, Urquhart, G, Bielawski, J, Finnegan, M & Petty, R 2015, 'Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer', BMC Cancer, vol. 15, no. 1, 762. https://doi.org/10.1186/s12885-015-1718-7

    Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer. / Matula, Kasia; Collie-Duguid, Elaina; Murray, Graeme; Parikh, Khyati; Grabsch, Heike; Tan, Patrick; Lalwani, Salina; Garau, Roberta; Ong, Yuhan; Bain, Gillian; Smith, Asa-Dahle; Urquhart, Gordon; Bielawski, Jacek; Finnegan, Michael; Petty, Russell.

    In: BMC Cancer, Vol. 15, No. 1, 762, 22.10.2015.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer

    AU - Matula, Kasia

    AU - Collie-Duguid, Elaina

    AU - Murray, Graeme

    AU - Parikh, Khyati

    AU - Grabsch, Heike

    AU - Tan, Patrick

    AU - Lalwani, Salina

    AU - Garau, Roberta

    AU - Ong, Yuhan

    AU - Bain, Gillian

    AU - Smith, Asa-Dahle

    AU - Urquhart, Gordon

    AU - Bielawski, Jacek

    AU - Finnegan, Michael

    AU - Petty, Russell

    PY - 2015/10/22

    Y1 - 2015/10/22

    N2 - BACKGROUND: Resistance to chemotherapy is common in gastroesophageal cancer. Mechanisms of resistance are incompletely characterised and there are no predictive biomarkers in clinical practice for cytotoxic drugs. We used new cell line models to characterise novel chemotherapy resistance mechanisms and validated them in tumour specimens to identify new targets and biomarkers for gastroesophageal cancer.METHODS: Cell lines were selected for resistance to oxaliplatin, cisplatin and docetaxel and gene expression examined using Affymetrix Exon 1.0 ST arrays. Leads were validated by qRT-PCR and HPLC of tumour metabolites. Protein expression and pharmacological inhibition of lead target SPHK1 was evaluated in independent cell lines, and by immunohistochemistry in gastroesophageal cancer patients.RESULTS: Genes with differential expression in drug resistant cell lines compared to the parental cell line they were derived from, were identified for each drug resistant cell line. Biological pathway analysis of these gene lists, identified over-represented pathways, and only 3 pathways - lysosome, sphingolipid metabolism and p53 signalling- were identified as over-represented in these lists for all three cytotoxic drugs investigated. The majority of genes differentially expressed in chemoresistant cell lines from these pathways, were involved in metabolism of glycosphingolipids and sphingolipids in lysosomal compartments suggesting that sphingolipids might be important mediators of cytotoxic drug resistance in gastroeosphageal cancers . On further investigation, we found that drug resistance (IC50) was correlated with increased sphingosine kinase 1(SPHK1) mRNA and also with decreased sphingosine-1-phosphate lysase 1(SGPL1) mRNA. SPHK1 and SGPL1 gene expression were inversely correlated. SPHK1:SGPL1 ratio correlated with increased cellular sphingosine-1-phosphate (S1P), and S1P correlated with drug resistance (IC50). High SPHK1 protein correlated with resistance to cisplatin (IC50) in an independent gastric cancer cell line panel and with survival of patients treated with chemotherapy prior to surgery but not in patients treated with surgery alone. Safingol a SPHK1 inhibitor, was cytotoxic as a single agent and acted synergistically with cisplatin in gastric cancer cell lines.CONCLUSION: Agents that inhibit SPHK1 or S1P could overcome cytotoxic drug resistance in gastroesophageal cancer. There are several agents in early phase human trials including Safingol that could be combined with chemotherapy or used in patients progressing after chemotherapy.

    AB - BACKGROUND: Resistance to chemotherapy is common in gastroesophageal cancer. Mechanisms of resistance are incompletely characterised and there are no predictive biomarkers in clinical practice for cytotoxic drugs. We used new cell line models to characterise novel chemotherapy resistance mechanisms and validated them in tumour specimens to identify new targets and biomarkers for gastroesophageal cancer.METHODS: Cell lines were selected for resistance to oxaliplatin, cisplatin and docetaxel and gene expression examined using Affymetrix Exon 1.0 ST arrays. Leads were validated by qRT-PCR and HPLC of tumour metabolites. Protein expression and pharmacological inhibition of lead target SPHK1 was evaluated in independent cell lines, and by immunohistochemistry in gastroesophageal cancer patients.RESULTS: Genes with differential expression in drug resistant cell lines compared to the parental cell line they were derived from, were identified for each drug resistant cell line. Biological pathway analysis of these gene lists, identified over-represented pathways, and only 3 pathways - lysosome, sphingolipid metabolism and p53 signalling- were identified as over-represented in these lists for all three cytotoxic drugs investigated. The majority of genes differentially expressed in chemoresistant cell lines from these pathways, were involved in metabolism of glycosphingolipids and sphingolipids in lysosomal compartments suggesting that sphingolipids might be important mediators of cytotoxic drug resistance in gastroeosphageal cancers . On further investigation, we found that drug resistance (IC50) was correlated with increased sphingosine kinase 1(SPHK1) mRNA and also with decreased sphingosine-1-phosphate lysase 1(SGPL1) mRNA. SPHK1 and SGPL1 gene expression were inversely correlated. SPHK1:SGPL1 ratio correlated with increased cellular sphingosine-1-phosphate (S1P), and S1P correlated with drug resistance (IC50). High SPHK1 protein correlated with resistance to cisplatin (IC50) in an independent gastric cancer cell line panel and with survival of patients treated with chemotherapy prior to surgery but not in patients treated with surgery alone. Safingol a SPHK1 inhibitor, was cytotoxic as a single agent and acted synergistically with cisplatin in gastric cancer cell lines.CONCLUSION: Agents that inhibit SPHK1 or S1P could overcome cytotoxic drug resistance in gastroesophageal cancer. There are several agents in early phase human trials including Safingol that could be combined with chemotherapy or used in patients progressing after chemotherapy.

    U2 - 10.1186/s12885-015-1718-7

    DO - 10.1186/s12885-015-1718-7

    M3 - Article

    VL - 15

    JO - BMC Cancer

    JF - BMC Cancer

    SN - 1471-2407

    IS - 1

    M1 - 762

    ER -