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

Overview of attention for article published in BMC Cancer, October 2015
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About this Attention Score

  • Above-average Attention Score compared to outputs of the same age (64th percentile)
  • Good Attention Score compared to outputs of the same age and source (77th percentile)

Mentioned by

patent
1 patent

Citations

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36 Dimensions

Readers on

mendeley
55 Mendeley
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Title
Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer
Published in
BMC Cancer, October 2015
DOI 10.1186/s12885-015-1718-7
Pubmed ID
Authors

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

Abstract

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. 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. 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. 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.

Mendeley readers

The data shown below were compiled from readership statistics for 55 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Spain 1 2%
Unknown 54 98%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 11 20%
Student > Bachelor 9 16%
Researcher 8 15%
Student > Master 7 13%
Professor 3 5%
Other 9 16%
Unknown 8 15%
Readers by discipline Count As %
Medicine and Dentistry 12 22%
Biochemistry, Genetics and Molecular Biology 11 20%
Agricultural and Biological Sciences 10 18%
Pharmacology, Toxicology and Pharmaceutical Science 3 5%
Immunology and Microbiology 2 4%
Other 7 13%
Unknown 10 18%

Attention Score in Context

This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 21 February 2019.
All research outputs
#4,581,651
of 14,826,751 outputs
Outputs from BMC Cancer
#1,234
of 5,602 outputs
Outputs of similar age
#90,153
of 283,388 outputs
Outputs of similar age from BMC Cancer
#154
of 763 outputs
Altmetric has tracked 14,826,751 research outputs across all sources so far. This one is in the 49th percentile – i.e., 49% of other outputs scored the same or lower than it.
So far Altmetric has tracked 5,602 research outputs from this source. They receive a mean Attention Score of 4.0. This one has gotten more attention than average, scoring higher than 71% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 283,388 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 64% of its contemporaries.
We're also able to compare this research output to 763 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 77% of its contemporaries.