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Journal of Ovarian Research
Published in: Journal of Ovarian Research 1/2015

Open Access 01-12-2015 | Research

A metabolomic approach to identifying platinum resistance in ovarian cancer

Authors: Laila M Poisson, Adnan Munkarah, Hala Madi, Indrani Datta, Sharon Hensley-Alford, Calvin Tebbe, Thomas Buekers, Shailendra Giri, Ramandeep Rattan

Published in: Journal of Ovarian Research | Issue 1/2015

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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.
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Literature
1.
2.
Matsuo K, Eno ML, Im DD, Rosenshein NB, Sood AK. Clinical relevance of extent of extreme drug resistance in epithelial ovarian carcinoma. Gynecol Oncol. 2010;116:61–5.CrossRefPubMedCentralPubMed
3.
Zwelling LA, Kohn KW. Mechanism of action of cis-dichlorodiammineplatinum(II). Cancer Treat Rep. 1979;63:1439–44.PubMed
4.
Mandic A, Hansson J, Linder S, Shoshan MC. Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. J Biol Chem. 2003;278:9100–6.CrossRefPubMed
5.
Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31:1869–83.CrossRefPubMed
6.
7.
Parker RJ, Eastman A, Bostick-Bruton F, Reed E. Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation. J Clin Invest. 1991;87:772–7.CrossRefPubMedCentralPubMed
8.
9.
Slupsky CM, Steed H, Wells TH, Dabbs K, Schepansky A, Capstick V, et al. Urine metabolite analysis offers potential early diagnosis of ovarian and breast cancers. Clin Cancer Res. 2010;16:5835–41.CrossRefPubMed
10.
Chen J, Zhou L, Zhang X, Lu X, Cao R, Xu C, et al. Urinary hydrophilic and hydrophobic metabolic profiling based on liquid chromatography-mass spectrometry methods: Differential metabolite discovery specific to ovarian cancer. Electrophoresis. 2012;33:3361–9.CrossRefPubMed
11.
Zhang T, Wu X, Ke C, Yin M, Li Z, Fan L, et al. Identification of potential biomarkers for ovarian cancer by urinary metabolomic profiling. J Proteome Res. 2013;12:505–12.CrossRefPubMed
12.
Fan L, Zhang W, Yin M, Zhang T, Wu X, Zhang H, et al. Identification of metabolic biomarkers to diagnose epithelial ovarian cancer using a UPLC/QTOF/MS platform. Acta Oncol. 2012;51:473–9.CrossRefPubMed
13.
Fong MY, McDunn J, Kakar SS. Identification of metabolites in the normal ovary and their transformation in primary and metastatic ovarian cancer. PLoS One. 2011;6:e19963.CrossRefPubMedCentralPubMed
14.
Asiago VM, Alvarado LZ, Shanaiah N, Gowda GA, Owusu-Sarfo K, Ballas RA, et al. Early detection of recurrent breast cancer using metabolite profiling. Cancer Res. 2010;70:8309–18.CrossRefPubMedCentralPubMed
15.
Yamaguchi R, Janssen E, Perkins G, Ellisman M, Kitada S, Reed JC. Efficient elimination of cancer cells by deoxyglucose-ABT-263/737 combination therapy. PLoS One. 2011;6:e24102.CrossRefPubMedCentralPubMed
16.
Menendez JA, Lupu R, Colomer R. Inhibition of tumor-associated fatty acid synthase hyperactivity induces synergistic chemosensitization of HER −2/ neu -overexpressing human breast cancer cells to docetaxel (taxotere). Breast Cancer Res Treat. 2004;84:183–95.CrossRefPubMed
17.
Cao X, Fang L, Gibbs S, Huang Y, Dai Z, Wen P, et al. Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia. Cancer Chemother Pharmacol. 2007;59:495–505.CrossRefPubMed
18.
von Stechow L, Ruiz-Aracama A, van de Water B, Peijnenburg A, Danen E, Lommen A. Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells. PLoS One. 2013;8:e76476.CrossRef
19.
Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009;457:910–4.CrossRefPubMedCentralPubMed
20.
Boudonck KJ, Mitchell MW, Nemet L, Keresztes L, Nyska A, Shinar D, et al. Discovery of metabolomics biomarkers for early detection of nephrotoxicity. Toxicol Pathol. 2009;37:280–92.CrossRefPubMed
21.
Evans AM, DeHaven CD, Barrett T, Mitchell M, Milgram E. Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. Anal Chem. 2009;81:6656–67.CrossRefPubMed
22.
Lawton KA, Berger A, Mitchell M, Milgram KE, Evans AM, Guo L, et al. Analysis of the adult human plasma metabolome. Pharmacogenomics. 2008;9:383–97.CrossRefPubMed
23.
Johnson SW, Perez RP, Godwin AK, Yeung AT, Handel LM, Ozols RF, et al. Role of platinum-DNA adduct formation and removal in cisplatin resistance in human ovarian cancer cell lines. Biochem Pharmacol. 1994;47:689–97.CrossRefPubMed
24.
Kanehisa M, Goto S, Furumichi M, Tanabe M, Hirakawa M. KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res. 2010;38:D355–60.CrossRefPubMedCentralPubMed
25.
Xia J, Psychogios N, Young N, Wishart DS. MetaboAnalyst: a web server for metabolomic data analysis and interpretation. Nucleic Acids Res. 2009;37:W652–60.CrossRefPubMedCentralPubMed
26.
Goeman JJ, van de Geer SA, de Kort F, van Houwelingen HC. A global test for groups of genes: testing association with a clinical outcome. Bioinformatics. 2004;20:93–9.CrossRefPubMed
27.
Balmanno K, Cook SJ. Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ. 2009;16:368–77.CrossRefPubMed
28.
29.
Salway JG. Amino Acid Metabolism, Folate Metabolism and The’1-carbon pool’ I: Purine Biosynthesis. In: Metabolism at a Glance. Malden, MA: Blackwell Publishing; 2004. p. 94–5.
30.
31.
Modis K, Coletta C, Asimakopoulou A, Szczesny B, Chao C, Papapetropoulos A, et al. Effect of S-adenosyl-l-methionine (SAM), an allosteric activator of cystathionine-beta-synthase (CBS) on colorectal cancer cell proliferation and bioenergetics in vitro. Nitric Oxide. 2014;41:146–56.CrossRefPubMed
32.
Ham MS, Lee JK, Kim KC. S-adenosyl methionine specifically protects the anticancer effect of 5-FU via DNMTs expression in human A549 lung cancer cells. Mol Clin Oncol. 2013;1:373–8.PubMedCentralPubMed
33.
Sinha R, Cooper TK, Rogers CJ, Sinha I, Turbitt WJ, Calcagnotto A, et al. Dietary methionine restriction inhibits prostatic intraepithelial neoplasia in TRAMP mice. Prostate. 2014;74:1663–73.CrossRefPubMed
34.
Strekalova E, Malin D, Good DM, Cryns VL: Methionine Deprivation Induces a Targetable Vulnerability in Triple-negative Breast Cancer Cells by Enhancing TRAIL Receptor-2 Expression. Clin Cancer Res 2015; Feb 27 [Epub ahead of print]
35.
Mecham JO, Rowitch D, Wallace CD, Stern PH, Hoffman RM. The metabolic defect of methionine dependence occurs frequently in human tumor cell lines. Biochem Biophys Res Commun. 1983;117:429–34.CrossRefPubMed
36.
Liu H, Zhang W, Wang K, Wang X, Yin F, Li C, et al. Methionine and cystine double deprivation stress suppresses glioma proliferation via inducing ROS/autophagy. Toxicol Lett. 2015;232:349–55.CrossRefPubMed
37.
Cellarier E, Durando X, Vasson MP, Farges MC, Demiden A, Maurizis JC, et al. Methionine dependency and cancer treatment. Cancer Treat Rev. 2003;29:489–99.CrossRefPubMed
38.
Cavuoto P, Fenech MF. A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension. Cancer Treat Rev. 2012;38:726–36.CrossRefPubMed
39.
Mathews CK, van Holde KE, Ahern KG. Metabolism of nitrogenous compounds: amino acids, porphyrins, and neurotransmitters. In: Biochemistry. 3rd ed. San Francisco: Addison Wesley Longman; 1999. p. 743–93.
40.
Bertino JR, Waud WR, Parker WB, Lubin M. Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity: current strategies. Cancer Biol Ther. 2011;11:627–32.CrossRefPubMedCentralPubMed
41.
42.
Traverso N, Ricciarelli R, Nitti M, Marengo B, Furfaro AL, Pronzato MA, et al. Role of glutathione in cancer progression and chemoresistance. Oxid Med Cell Longev. 2013;2013:972913.PubMedCentralPubMed
43.
Balendiran GK, Dabur R, Fraser D. The role of glutathione in cancer. Cell Biochem Funct. 2004;22:343–52.CrossRefPubMed
44.
Yang Y, Bedford MT. Protein arginine methyltransferases and cancer. Nat Rev Cancer. 2013;13:37–50.CrossRefPubMed
45.
Barton CA, Hacker NF, Clark SJ, O’Brien PM. DNA methylation changes in ovarian cancer: implications for early diagnosis, prognosis and treatment. Gynecol Oncol. 2008;109:129–39.CrossRefPubMed
46.
Koukoura O, Spandidos DA, Daponte A, Sifakis S. DNA methylation profiles in ovarian cancer: implication in diagnosis and therapy (Review). Mol Med Rep. 2014;10:3–9.PubMedCentralPubMed
47.
Kartalou M, Essigmann JM. Recognition of cisplatin adducts by cellular proteins. Mutat Res. 2001;478:1–21.CrossRefPubMed
48.
Wang D, Lippard SJ. Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov. 2005;4:307–20.CrossRefPubMed
49.
Zeller C, Dai W, Steele NL, Siddiq A, Walley AJ, Wilhelm-Benartzi CS, et al. Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling. Oncogene. 2012;31:4567–76.CrossRefPubMed
50.
Mandal S, Mandal A, Johansson HE, Orjalo AV, Park MH. Depletion of cellular polyamines, spermidine and spermine, causes a total arrest in translation and growth in mammalian cells. Proc Natl Acad Sci U S A. 2013;110:2169–74.CrossRefPubMedCentralPubMed
51.
Snyder SH, Russell DH. Polyamine synthesis in rapidly growing tissues. Fed Proc. 1970;29:1575–82.PubMed
52.
53.
Casero Jr RA, Marton LJ. Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat Rev Drug Discov. 2007;6:373–90.CrossRefPubMed
54.
Verma AK. Polyamines and cancer. In: Polyamine Cell Signaling: Physiology, Pharmacology, and cancer reserach. New York City, NY: Humana Press; 2006. p. 313–77.CrossRef
55.
Pegg AE. Spermidine/spermine-N(1)-acetyltransferase: a key metabolic regulator. Am J Physiol Endocrinol Metab. 2008;294:E995–1010.CrossRefPubMed
56.
Bettuzzi S, Davalli P, Astancolle S, Carani C, Madeo B, Tampieri A, et al. Tumor progression is accompanied by significant changes in the levels of expression of polyamine metabolism regulatory genes and clusterin (sulfated glycoprotein 2) in human prostate cancer specimens. Cancer Res. 2000;60:28–34.PubMed
57.
Corona G, Toffoli G, Fabris M, Viel A, Zarrelli A, Donada C, et al. Homocysteine accumulation in human ovarian carcinoma ascitic/cystic fluids possibly caused by metabolic alteration of the methionine cycle in ovarian carcinoma cells. Eur J Cancer. 1997;33:1284–90.CrossRefPubMed
58.
Stabler S, Koyama T, Zhao Z, Martinez-Ferrer M, Allen RH, Luka Z, et al. Serum methionine metabolites are risk factors for metastatic prostate cancer progression. PLoS One. 2011;6:e22486.CrossRefPubMedCentralPubMed
59.
Yoo CB, Jones PA. Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov. 2006;5:37–50.CrossRefPubMed
60.
Rodriguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med. 2011;17:330–9.CrossRefPubMed
61.
Stresemann C, Brueckner B, Musch T, Stopper H, Lyko F. Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines. Cancer Res. 2006;66:2794–800.CrossRefPubMed
62.
Spannhoff A, Hauser AT, Heinke R, Sippl W, Jung M. The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. ChemMedChem. 2009;4:1568–82.CrossRefPubMed
63.
Shan L, Chen YA, Davis L, Han G, Zhu W, Molina AD, et al. Measurement of phospholipids may improve diagnostic accuracy in ovarian cancer. PLoS One. 2012;7:e46846.CrossRefPubMedCentralPubMed
64.
Pua TL, Wang FQ, Fishman DA. Roles of LPA in ovarian cancer development and progression. Future Oncol. 2009;5:1659–73.CrossRefPubMed
65.
Metadata
Title
A metabolomic approach to identifying platinum resistance in ovarian cancer
Authors
Laila M Poisson
Adnan Munkarah
Hala Madi
Indrani Datta
Sharon Hensley-Alford
Calvin Tebbe
Thomas Buekers
Shailendra Giri
Ramandeep Rattan
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2015
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/s13048-015-0140-8

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