A metabolomic approach to identifying platinum resistance in ovarian cancer

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Abstract

Background

Acquisition of metabolic alterations has been shown to be essential for the unremitting growth of cancer, yet the relation of such alterations to chemosensitivity has not been investigated. In the present study our aim was to identify the metabolic alterations that are specifically associated with platinum resistance in ovarian cancer. A global metabolic analysis of the A2780 platinum-sensitive and its platinum-resistant derivative C200 ovarian cancer cell line was performed utilizing ultra-high performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy. Per-metabolite comparisons were made between cell lines and an interpretive analysis was carried out using the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic library and the Ingenuity exogenous molecule library.

Results

We observed 288 identified metabolites, of which 179 were found to be significantly different ( t-test p < 0.05) between A2780 and C200 cells. Of these, 70 had increased and 109 had decreased levels in platinum resistant C200 cells. The top altered KEGG pathways based on number or impact of alterations involved the cysteine and methionine metabolism. An Ingenuity Pathway Analysis also revealed that the methionine degradation super-pathway and cysteine biosynthesis are the top two canonical pathways affected. The highest scoring network of altered metabolites was related to carbohydrate metabolism, energy production, and small molecule biochemistry. Compilation of KEGG analysis and the common network molecules revealed methionine and associated pathways of glutathione synthesis and polyamine biosynthesis to be most significantly altered.

Conclusion

Our findings disclose that the chemoresistant C200 ovarian cancer cells have distinct metabolic alterations that may contribute to its platinum resistance. This distinct metabolic profile of platinum resistance is a first step towards biomarker development for the detection of chemoresistant disease and metabolism-based drug targets specific for chemoresistant tumors.

Electronic supplementary material

The online version of this article (doi:10.1186/s13048-015-0140-8) contains supplementary material, which is available to authorized users.

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Most cited references 42

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MetaboAnalyst: a web server for metabolomic data analysis and interpretation

Jianguo Xia, Nick Psychogios, Nelson Young … (2009)

Metabolomics is a newly emerging field of ‘omics’ research that is concerned with characterizing large numbers of metabolites using NMR, chromatography and mass spectrometry. It is frequently used in biomarker identification and the metabolic profiling of cells, tissues or organisms. The data processing challenges in metabolomics are quite unique and often require specialized (or expensive) data analysis software and a detailed knowledge of cheminformatics, bioinformatics and statistics. In an effort to simplify metabolomic data analysis while at the same time improving user accessibility, we have developed a freely accessible, easy-to-use web server for metabolomic data analysis called MetaboAnalyst. Fundamentally, MetaboAnalyst is a web-based metabolomic data processing tool not unlike many of today's web-based microarray analysis packages. It accepts a variety of input data (NMR peak lists, binned spectra, MS peak lists, compound/concentration data) in a wide variety of formats. It also offers a number of options for metabolomic data processing, data normalization, multivariate statistical analysis, graphing, metabolite identification and pathway mapping. In particular, MetaboAnalyst supports such techniques as: fold change analysis, t-tests, PCA, PLS-DA, hierarchical clustering and a number of more sophisticated statistical or machine learning methods. It also employs a large library of reference spectra to facilitate compound identification from most kinds of input spectra. MetaboAnalyst guides users through a step-by-step analysis pipeline using a variety of menus, information hyperlinks and check boxes. Upon completion, the server generates a detailed report describing each method used, embedded with graphical and tabular outputs. MetaboAnalyst is capable of handling most kinds of metabolomic data and was designed to perform most of the common kinds of metabolomic data analyses. MetaboAnalyst is accessible at http://www.metaboanalyst.ca

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Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.

Arun Sreekumar, Laila Poisson, Thekkelnaycke M Rajendiran … (2009)

Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.

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Role of Glutathione in Cancer Progression and Chemoresistance

Nicola Traverso, Roberta Ricciarelli, Mariapaola Nitti … (2013)

Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and disturbances in GSH homeostasis are involved in the etiology and progression of many human diseases including cancer. While GSH deficiency, or a decrease in the GSH/glutathione disulphide (GSSG) ratio, leads to an increased susceptibility to oxidative stress implicated in the progression of cancer, elevated GSH levels increase the antioxidant capacity and the resistance to oxidative stress as observed in many cancer cells. The present review highlights the role of GSH and related cytoprotective effects in the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.

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Author and article information

Contributors

Laila M Poisson: lpoisso1@hfhs.org

Adnan Munkarah: amunkar1@hfhs.org

Hala Madi: hmadi1@hfhs.org

Indrani Datta: idatta1@hfhs.org

Sharon Hensley-Alford: salford1@hfhs.org

Calvin Tebbe: ctebbe87@gmail.com

Thomas Buekers: tbueker1@hfhs.org

Shailendra Giri: sgiri1@hfhs.org

Ramandeep Rattan: rrattan1@hfhs.org

Journal

Journal ID (nlm-ta): J Ovarian Res

Journal ID (iso-abbrev): J Ovarian Res

Title: Journal of Ovarian Research

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-2215

Publication date (Electronic): 26 March 2015

Publication date PMC-release: 26 March 2015

Publication date Collection: 2015

Volume: 8

Electronic Location Identifier: 13

Affiliations

[ ]Center for Bioinformatics, Henry Ford Hospital, Detroit, MI 48202 USA

[ ]Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI 48202 USA

[ ]Josephine Ford Cancer Institute, Henry Ford Hospital, Detroit, MI 48202 USA

[ ]Division of Gynecology Oncology, Department of Women’s Health Services, Henry Ford Hospital, Detroit, MI 48202 USA

[ ]Department of Neurology, Henry Ford Health System, Detroit, MI 48202 USA

Article

Publisher ID: 140

DOI: 10.1186/s13048-015-0140-8

PMC ID: 4396147

PubMed ID: 25880539

SO-VID: e2420a17-e41c-45ce-8673-0ed03ef72652

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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.

History

Date received : 18 December 2014

Date accepted : 9 March 2015

Custom metadata

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: metabolomics,ovarian cancer,platinum resistance,a2780,c200,methionine metabolism

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ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: metabolomics, ovarian cancer, platinum resistance, a2780, c200, methionine metabolism

A metabolomic approach to identifying platinum resistance in ovarian cancer

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Karger: Oncology

Most cited references 42

MetaboAnalyst: a web server for metabolomic data analysis and interpretation

Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.

Role of Glutathione in Cancer Progression and Chemoresistance

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