Cancer and arachidonic acid (AA) have important linkages. For example, AA metabolites regulate several critical biological functions associated with carcinogenesis: angiogenesis, apoptosis, and cancer invasion. However, little is known about the comparative changes in metabolite expression of the arachidonic acid pathway (AAP) in carcinogenesis. In this study, we examined transcriptome data from 12 cancers, such as breast invasive carcinoma, colon adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma. We also report here a reverse-engineering strategy wherein we estimated metabolic signatures associated with AAP by (1) making deductive inferences through transcriptome-level data extraction, (2) remodeling AA metabolism, and (3) performing a comparative analysis of cancer types to determine the similarities and differences between different cancer types with respect to AA metabolic alterations. We identified 77 AAP gene signatures differentially expressed in cancers and 37 AAP metabolites associated with them. Importantly, the metabolite 15(S)-HETE was identified in almost all cancers, while arachidonate, 5-HETE, PGF2α, 14,15-EET, 8,9-EET, 5,6-EET, and 20-HETE were discovered as other most regulated metabolites. This study shows that the 12 cancers studied herein, although in different branches of the AAP, have altered expression of AAP gene signatures. Going forward, AA related-cancer research generally, and the molecular signatures and their estimated metabolites reported herein specifically, hold broad promise for precision/personalized medicine in oncology as potential therapeutic and diagnostic targets.
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References
1.
Aguirre-GamboaR, Gomez-RuedaH, Martínez-LedesmaE, et al.SurvExpress: An online biomarker validation tool and database for cancer gene expression data using survival analysis. PLoS One, 2013; 8(9):e74250; doi: 10.1371/journal.pone.0074250
2.
AlexanianA, MillerB, RomanRJ, et al. 20-HETE-producing enzymes are up-regulated in human cancers. Cancer Genomics Proteomics, 2012; 9(4):163–169.
3.
AvisI, HongSH, MartínezA, et al.Five-lipoxygenase inhibitors can mediate apoptosis in human breast cancer cell lines through complex eicosanoid interactions. FASEB J, 2001; 15(11):2007–2009; doi: 10.1096/fj.00-0866fje
4.
BarnesN, HaywoodP, FlintP, et al.Survivin expression in in situ and invasive breast cancer relates to COX-2 expression and DCIS recurrence. Br J Cancer, 2006; 94(2):253–258; doi: 10.1038/sj.bjc.6602932
5.
BorinTF, ShankarA, AngaraK, et al.HET0016 decreases lung metastasis from breast cancer in immune-competent mouse model. PLoS One, 2017; 12(6):e0178830; doi: 10.1371/journal.pone.0178830
6.
BorinTF, ZuccariDAPC, Jardim-PerassiBV, et al.HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice. PLoS One, 2014; 9(12):e116247; doi: 10.1371/journal.pone.0116247
7.
BrandA, EvangelatosN, ÖzdemirV. Placebogenomics: A new concept and tool for personalized medicine and public health. OMICS, 2021; 25(2):76–78; doi: 10.1089/omi.2020.0221
8.
CabralGA. Lipids as bioeffectors in the immune system. Life Sci, 2005; 9;77(14):1699–1710; doi: 10.1016/j.lfs.2005.05.013
9.
CebolaI, PeinadoMA. Epigenetic deregulation of the COX pathway in cancer. Prog Lipid Res, 2012; 51(4):301–313; doi: 10.1016/j.plipres.2012.02.005
10.
ChanAT, OginoS, FuchsCS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med, 2007; 356(21):2131–2142; doi: 10.1056/NEJMoa067208
11.
ChanTA, MorinPJ, VogelsteinB, et al.Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis. Med Sci, 1998; 95:681–686; doi: 10.1073/pnas.95.2.681
12.
ChenC, WeiX, RaoX, et al.Cytochrome P450 2J2 is highly expressed in hematologic malignant diseases and promotes tumor cell growth. J Pharmacol Exp Ther, 2011; 336(2):344–355; doi: 10.1124/jpet.110.174805
13.
ChengL, JiangJ, SunZ, et al.The epoxyeicosatrienoic acid-stimulated phosphorylation of EGF-R involves the activation of metalloproteinases and the release of HB-EGF in cancer cells. Acta Pharmacol Sin, 2010; 31(2):211–218; doi: 10.1038/aps.2009.184
14.
ColapricoA, SilvaTC, OlsenC, et al.TCGAbiolinks: An R/bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res, 2016; 44(8):e71–e71; doi: 10.1093/nar/gkv1507
15.
CuendetM, PezzutoJM. The role of cyclooxygenase and lipoxygenase in cancer chemoprevention. Drug Metabol Drug Interact, 2000; 17(1–4):109–157; doi: 10.1515/dmdi.2000.17.1–4.109
16.
DuY, ZhaoH-C, ZhuH-C, et al.Ferroptosis is involved in the anti tumor effect of lycorine in renal cell carcinoma cells. Oncol Lett, 2021; 22(5):1–9; doi: 10.3892/ol.2021.13042
17.
FunkCD. Prostaglandins and leukotrienes: Advances in eicosanoid biology. Science (1979), 2001; 294(5548):1871–1875; doi: 10.1126/science.294.5548.1871
18.
GentlemanRC, CareyVJ, BatesDM, et al.Bioconductor: Open software development for computational biology and bioinformatics. Genome Biol, 2004; 5(10):1–16; doi: 10.1186/gb-2004-5-10-r80
19.
GhoshJ, MyersCE. Arachidonic acid stimulates prostate cancer cell growth: Critical role of 5-lipoxygenase. Biochem Biophys Res Commun, 1997; 235(2):418–423; doi: 10.1006/bbrc.1997.6799
20.
GolubnitschajaO, BabanB, BonioloG, et al.Medicine in the early twenty-first century: Paradigm and anticipation—EPMA Position Paper 2016. EPMA J, 2016; 7(1): 23; doi: 10.1186/s13167-016-0072-4
21.
GolubnitschajaO, WatsonID, TopicE, et al.Position Paper of the EPMA and EFLM: A global vision of the consolidated promotion of an integrative medical approach to advance health care. EPMA J, 2013; 4(1):12; doi: 10.1186/1878-5085-4-12
HarrisRC, JacobsonHR, CapdevilaJ, et al.Epoxyeicosatrienoic acids activate Na+/H+ exchange and are mitogenic in cultured rat glomerular mesangial cells. J Cell Physiol, 1990; 144(3):429–437; doi: https://doi.org/10.1002/jcp.1041440310
24.
HasegawaK, ToriiY, IshiiR, et al.EVects of a selective COX-2 inhibitor in patients with uterine endometrial cancers. Arch Gynecol Obstet, 2011; 284:1515–1521; doi: 10.1007/s00404-011-1883-0
25.
HerwigR, HardtC, LienhardM, et al.Analyzing and interpreting genome data at the network level with ConsensusPathDB. Nat Protoc, 2016; 11(10):1889–1907; doi: 10.1038/nprot.2016.117
26.
HigginsAJ, LeesP. The acute inflammatory process, arachidonic acid metabolism and the mode of action of anti-inflammatory drugs. Equine Vet J, 1984; 16(3):163–175; doi: 10.1111/j.2042–3306.1984.tb01893.x
27.
HirschFR, LippmanSM. Advances in the biology of lung cancer chemoprevention. J Clin Oncol, 2005; 23(14):3186–3197; doi: 10.1200/JCO.2005.14.209
28.
HornT, AdelS, SchumannR, et al.Evolutionary aspects of lipoxygenases and genetic diversity of human leukotriene signaling. Prog Lipid Res, 2015; 57:13–39; doi: 10.1016/j.plipres.2014.11.001
29.
HydeCAC, MissailidisS. Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis. Int Immunopharmacol, 2009; 9(6):701–715; doi: 10.1016/J.INTIMP.2009.02.003
30.
Jara-Gutiérrez Á, BaladrónV. The role of prostaglandins in different types of cancer. Cells, 2021; 10(6):1487; doi: 10.3390/cells10061487
31.
JayadevS, HayterHL, AndrieuN, et al.Phospholipase A 2 is necessary for tumor necrosis factor A-Induced ceramide generation in L929 Cells*. J Biol Chem, 1997; 272(27):17196–17203; doi: 10.1074/jbc.272.27.17196
32.
JiangJ-G, NingY-G, ChenC, et al.Cytochrome P450 epoxygenase promotes human cancer metastasis. Cancer Res, 2007; 67(14):6665–6674; doi: 10.1158/0008-5472.CAN-06-3643
33.
JiangWG, Douglas-JonesA, ManselRE. Levels of expression of lipoxygenases and cyclooxygenase-2 in human breast cancer. Prostaglandins Leukot Essent Fatty Acids, 2003; 69(4):275–281; doi: 10.1016/S0952-3278(03)00110-8
34.
KanehisaM, GotoS. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res, 2000; 28(1):27–30; doi: 10.1093/nar/28.1.27
35.
KarpishehV, NikkhooA, Hojjat-FarsangiM, et al.Prostaglandin E2 as a potent therapeutic target for treatment of colon cancer. Prostaglandins Other Lipid Mediat, 2019; 144(March):106338; doi: 10.1016/j.prostaglandins.2019.106338
36.
KrysanK, DalwadiH, SharmaS, et al.Cyclooxygenase 2-dependent expression of survivin is critical for apoptosis resistance in non-small cell lung cancer. Adv Brief, 2004; 64:6359–6362; doi: 10.1158/0008-5472.CAN-04-1681
37.
KusmartsevS. Enhanced 15-lipoxygenase activity and elevated eicosanoid production in kidney tumor microenvironment contribute to the inflammation and immune suppression. Oncoimmunology, 2012; 1(2):249–251; doi: 10.4161/onci.1.2.18502
38.
LeeSIL, ZuoX, ShureiqiI. 15-Lipoxygenase-1 as a tumor suppressor gene in colon cancer: Is the verdict in?. Cancer Metastasis Rev, 2011; 30(3–4):481–491; doi: 10.1007/s10555-011-9321-0
39.
LiberzonA, BirgerC, ThorvaldsdóttirH, et al.The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst, 2015; 1(6):417–425; doi: 10.1016/j.cels.2015.12.004
40.
LiuJ, MazzonePJ, CataJP, et al.Serum free fatty acid biomarkers of lung cancer. Chest, 2014; 146(3):670–679; doi: 10.1378/chest.13-2568
41.
LoveMI, HuberW, AndersS. Moderated estimation of fold change and dispersion for RNA-Seq data with DESeq2. Genome Biol, 2014; 15(12):1–21; doi: 10.1186/s13059-014-0550-8
42.
MaQ, AduaE, BoyceMC, et al. IMass time: The future, in future! OMICS, 2018; 22(11):679–695; doi: 10.1089/omi.2018.0162
43.
MashimaR, OkuyamaT. The role of lipoxygenases in pathophysiology; New insights and future perspectives. Redox Biol, 2015; 6:297–310; doi: 10.1016/j.redox.2015.08.006
44.
MayuriM, KrishnamurthyPT, VijayakumarTM. NK1 receptor antagonistic effect of 17-trifluoromethyl phenyl trinor prostaglandin F2α on the growth of human breast cancer cell line. Exp Mol Pathol, 2022; 127:104817; doi: 10.1016/j.yexmp.2022.104817
45.
MoritaI. Distinct functions of COX-1 and COX-2. Prostaglandins Other Lipid Mediat, 2002; 68–69:165–175; doi: 10.1016/S0090-6980(02)00029-1
46.
NieD, NemethJ, QiaoY, et al.Increased metastatic potential in human prostate carcinoma cells by overexpression of arachidonate 12-lipoxygenase. Clin Exp Metastasis, 2003; 20:657–663; doi: 10.1023/a:1027302408187
47.
NithipatikomK, IsbellMA, SeeWA, et al.Elevated 12-and 20-hydroxyeicosatetraenoic acid in urine of patients with prostatic diseases. Cancer Lett, 2006; 233(2):219–225; doi: 10.1016/j.canlet.2005.03.025
48.
O'CallaghanG, HoustonA. Prostaglandin E2 and the EP receptors in malignancy: Possible therapeutic targets?. Br J Pharmacol, 2015; 172(22):5239–5250; doi: 10.1111/bph.13331
49.
OliveiraAP, PatilKR, NielsenJ. Architecture of transcriptional regulatory circuits is knitted over the topology of bio-molecular interaction networks. BMC Syst Biol, 2008; 2:17; doi: 10.1186/1752-0509-2-17
50.
OzdemirV. Precision medicine goes global: How to get it right? Four ways to mobilize scientific knowledge. OMICS, 2018; 22(8):539–543; doi: 10.1089/omi.2018.0104
51.
ÖzdemirV, ArgaKY, AzizRK, et al.Digging deeper into precision/personalized medicine: Cracking the sugar code, the third alphabet of life, and sociomateriality of the cell. OMICS, 2020; 24(2):62–80; doi: 10.1089/omi.2019.0220
52.
PanigrahyD, EdinML, LeeCR, et al.Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J Clin Invest, 2012; 122(1):178–191; doi: 10.1172/JCI58128
53.
PatrignaniP, TacconelliS, SciulliMG, et al.New insights into COX-2 biology and inhibition. Brain Res Rev, 2005; 48(2):352–359; doi: 10.1016/J.BRAINRESREV.2004.12.024
54.
PidgeonGP, LysaghtJ, KrishnamoorthyS, et al.Lipoxygenase metabolism: Roles in tumor progression and survival. Cancer Metastasis Rev, 2007; 26(3–4):503–524; doi: 10.1007/s10555-007-9098-3
55.
PrietoP, JaÉnRI, CalleD, et al.Interplay between post-translational cyclooxygenase-2 modifications and the metabolic and proteomic profile in a colorectal cancer cohort. World J Gastroenterol, 2019; 25(4):433–446; doi: 10.3748/wjg.v25.i4.433
56.
QualtroughD, KaidiA, ChellS, et al.Prostaglandin F2α stimulates motility and invasion in colorectal tumor cells. Int J Cancer, 2007; 121(4):734–740; doi: 10.1002/ijc.22755
57.
Raosaheb PatilK, NielsenJ. Uncovering transcriptional regulation of metabolism by using metabolic network topology. PNAS, 2005; 102(8):2685–2689; doi: 10.1073/pnas.0406811102
58.
ReeceAS. Extending the “Paracentral Dogma” of biology with the metabolome: Implications for understanding genomic–glycomic–metabolic–epigenomic synchronization. Engineering, 2022; doi: 10.1016/j.eng.2022.07.011
59.
RomanoM, ClàriaJ. Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: Implications for cancer therapy. FASEB J, 2003; 17(14):1986–1995; doi: 10.1096/fj.03-0053rev
60.
RothwellPM, WilsonM, ElwinCE, et al.Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-Year follow-up of five randomised trials. Lancet, 2010; 376(9754):1741–1750; doi: 10.1016/S0140-6736(10)61543-7
61.
ScottE, MunkleyJ. Glycans as biomarkers in prostate cancer. Int J Mol Sci, 2019; 20(6):1389; doi: 10.3390/ijms20061389
62.
SunS-Q, GuX, GaoX-S, et al.Overexpression of AKR1C3 significantly enhances human prostate cancer cells resistance to radiation. Oncotarget, 2016; 7(30):48050; doi: 10.18632/oncotarget.10347
63.
TangD-W, LinS-C, ChangK-W, et al.Elevated expression of cyclooxygenase (COX)-2 in oral squamous cell carcinoma—Evidence for COX-2 induction by areca quid ingredients in oral keratinocytes. J Oral Pathol Med, 2003; 32(9):522–529; doi: 10.1034/j.1600-0714.2003.00182.x
64.
TangJ, ZhangC, LinJ, et al.ALOX5-5-HETE promotes gastric cancer growth and alleviates chemotherapy toxicity via MEK/ERK activation. Cancer Med, 2021; 10(15):5246–5255; doi: 10.1002/cam4.4066
65.
VergoteIB, LaekemanGM, KeersmaekersGH, et al.Prostaglandin F2α in benign and malignant breast tumours. Br J Cancer, 1985; 51(6):827–836; doi: 10.1038/bjc.1985.128
66.
WangB, WuL, ChenJ, et al.Metabolism pathways of arachidonic acids: Mechanisms and potential therapeutic targets. Signal Transduct Target Ther, 2021; 6(1):94; doi: 10.1038/s41392-020-00443-w
WangT, FuX, ChenQ, et al.Arachidonic acid metabolism and kidney inflammation. Int J Mol Sci, 2019; 20(15):3683; doi: 10.3390/ijms20153683
69.
WangW. Glycomedicine: The current state of the art. Engineering, 2022; doi: 10.1016/j.eng.2022.03.009
70.
WangW, ÖzdemirV. Special issue: Glycomics and personalized glycomedicine. OMICS, 2019; 23(12):599–600; doi: 10.1089/omi.2019.0177
71.
YarlaNS, BishayeeA, SethiG, et al. Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin Cancer Biol, 2016; 40–41:48–81; doi: 10.1016/j.semcancer.2016.02.001
72.
YuW, ChenL, YangYQ, et al.Cytochrome P450 ω-hydroxylase promotes angiogenesis and metastasis by upregulation of VEGF and MMP-9 in non-small cell lung cancer. Cancer Chemother Pharmacol, 2011; 68(3):619–629; doi: 10.1007/s00280-010-1521-8
73.
YuanH, LiMY, MaLT, et al.15-Lipoxygenases and its metabolites 15(S)-HETE and 13(S)-HODE in the development of non-small cell lung cancer. Thorax, 2010; 65(4):321–326; doi: 10.1136/thx.2009.122747
74.
YuanJM, CarmellaSG, WangR, et al.Relationship of the oxidative damage biomarker 8-epiprostaglandin F2α to risk of lung cancer development in the Shanghai Cohort Study. Carcinogenesis, 2018; 39(7):948–954; doi: 10.1093/carcin/bgy060
75.
ZhangY, Nasrul HodaM, ZhengX, et al.Combined therapy with COX-2 inhibitor and 20-HETE inhibitor reduces colon tumor growth and the adverse effects of ischemic stroke associated with COX-2 inhibition. Am J Physiol Regul Integr Comp Physiol, 2014; 307:693–703; doi: 10.1152/ajpregu.00422.2013.-20-Hy
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