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, H I Grabsch, Patrick Tan, Salina Lalwani, Roberta Garau, Yuhan Ong, Gillian Bain, Asa Dahle-Smith, Gordon Urquhart, Jacek Bielawski, Michael Finnegan, Russell Petty (Corresponding Author)

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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 number762
Early online date22 Oct 2015
DOIs
Publication statusPublished - 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

Keywords

  • gastroesophageal cancer
  • chemoresistance
  • sphingosine-1-phosphate
  • sphingosine kinase 1

Cite this

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, H I; Tan, Patrick; Lalwani, Salina; Garau, Roberta; Ong, Yuhan; Bain, Gillian; Dahle-Smith, Asa; Urquhart, Gordon; Bielawski, Jacek; Finnegan, Michael; Petty, Russell (Corresponding Author).

In: BMC Cancer, Vol. 15, No. 762, 762, 2015.

Research output: Contribution to journalArticle

Matula, K, Collie-Duguid, E, Murray, G, Parikh, K, Grabsch, HI, Tan, P, Lalwani, S, Garau, R, Ong, Y, Bain, G, Dahle-Smith, A, 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. 762, 762. https://doi.org/10.1186/s12885-015-1718-7
Matula, Kasia ; Collie-Duguid, Elaina ; Murray, Graeme ; Parikh, Khyati ; Grabsch, H I ; Tan, Patrick ; Lalwani, Salina ; Garau, Roberta ; Ong, Yuhan ; Bain, Gillian ; Dahle-Smith, Asa ; 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. 762.
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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.",
keywords = "gastroesophageal cancer, chemoresistance, sphingosine-1-phosphate, sphingosine kinase 1",
author = "Kasia Matula and Elaina Collie-Duguid and Graeme Murray and Khyati Parikh and Grabsch, {H I} 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",
note = "Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Acknowledgements This work was funded by GASTROCAN (Grampian Gastroesophageal Cancer Research Fund), National Health Service Grampian Research and Development and the Jackie Strachan Research Fellowship. We would like to acknowledge the assistance of the NHS Grampian Bio-repository and are also are grateful to Nicky Fyfe and Dr Keith Stewart for assistance with immunohistochemistry. Financial Support This work was funded by grants to RP from GASTROCAN (Grampian Gastroesophageal Cancer Research Fund), National Health Service Grampian Research and Development and the Jackie Strachan Research Fellowship.",
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doi = "10.1186/s12885-015-1718-7",
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journal = "BMC Cancer",
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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, H I

AU - Tan, Patrick

AU - Lalwani, Salina

AU - Garau, Roberta

AU - Ong, Yuhan

AU - Bain, Gillian

AU - Dahle-Smith, Asa

AU - Urquhart, Gordon

AU - Bielawski, Jacek

AU - Finnegan, Michael

AU - Petty, Russell

N1 - Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Acknowledgements This work was funded by GASTROCAN (Grampian Gastroesophageal Cancer Research Fund), National Health Service Grampian Research and Development and the Jackie Strachan Research Fellowship. We would like to acknowledge the assistance of the NHS Grampian Bio-repository and are also are grateful to Nicky Fyfe and Dr Keith Stewart for assistance with immunohistochemistry. Financial Support This work was funded by grants to RP from GASTROCAN (Grampian Gastroesophageal Cancer Research Fund), National Health Service Grampian Research and Development and the Jackie Strachan Research Fellowship.

PY - 2015

Y1 - 2015

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.

KW - gastroesophageal cancer

KW - chemoresistance

KW - sphingosine-1-phosphate

KW - sphingosine kinase 1

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 - 762

M1 - 762

ER -