title: Inhibition of Prostaglandin Reductase 2, a Putative Oncogene Overexpressed in Human Pancreatic Adenocarcinoma, Induces Oxidative Stress-Mediated Cell Death Involving xCT and CTH Gene Expressions through 15-Keto-PGE2.
abstract: Prostaglandin reductase 2 (PTGR2) is the enzyme that catalyzes 15-keto-PGE2, an endogenous PPARγ ligand, into 13,14-dihydro-15-keto-PGE2. Previously, we have reported a novel oncogenic role of PTGR2 in gastric cancer, where PTGR2 was discovered to modulate ROS-mediated cell death and tumor transformation. In the present study, we demonstrated the oncogenic potency of PTGR2 in pancreatic cancer. First, we observed that the majority of the human pancreatic ductal adenocarcinoma tissues was stained positive for PTGR2 expression but not in the adjacent normal parts. In vitro analyses showed that silencing of PTGR2 expression enhanced ROS production, suppressed pancreatic cell proliferation, and promoted cell death through increasing 15-keto-PGE2. Mechanistically, silencing of PTGR2 or addition of 15-keto-PGE2 suppressed the expressions of solute carrier family 7 member 11 (xCT) and cystathionine gamma-lyase (CTH), two important providers of intracellular cysteine for the generation of glutathione (GSH), which is widely accepted as the first-line antioxidative defense. The oxidative stress-mediated cell death after silencing of PTGR2 or addition of 15-keto-PGE2 was further abolished after restoring intracellular GSH concentrations and cysteine supply by N-acetyl-L-cysteine and 2-Mercaptomethanol. Our data highlight the therapeutic potential of targeting PTGR2/15-keto-PGE2 for pancreatic cancer.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Emily Yun-Chia
authors.initials: EY
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan.|Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan.|Center for Obesity, Life style and Metabolic Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Forensic Medicine and Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.affiliation: Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Tien
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Tsai
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Siow-Wey
authors.initials: SW
authors.lastname: Hee
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ing-Jung
authors.initials: IJ
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Lee-Ming
authors.initials: LM
authors.lastname: Chuang
mesh_terms: D011452:15-Oxoprostaglandin 13-Reductase; D000426:Alcohol Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000502:physiology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress; D047495:PPAR gamma / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D047495:PPAR gamma; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; C026346:15-ketoprostaglandin E2; D000426:Alcohol Dehydrogenase; D011452:15-Oxoprostaglandin 13-Reductase; C485698:PTGR2 protein, human; D003542:Cystathionine gamma-Lyase; D005978:Glutathione; D015232:Dinoprostone
references.citation: Endocr Rev. 1999 Oct;20(5):649-88
references.pmid: 10529898
references.citation: Cell Death Differ. 2011 Mar;18(3):528-37
references.pmid: 20966963
references.citation: World J Gastroenterol. 2009 Aug 21;15(31):3874-83
references.pmid: 19701967
references.citation: FEBS Lett. 1999 Jul 16;455(1-2):135-9
references.pmid: 10428487
references.citation: Oncogene. 2014 Feb 6;33(6):771-82
references.pmid: 23353821
references.citation: World J Gastroenterol. 2009 Jan 28;15(4):441-8
references.pmid: 19152448
references.citation: Biochem Biophys Res Commun. 2015 Jun 26;462(2):85-90
references.pmid: 25944662
references.citation: PPAR Res. 2012;2012:367450
references.pmid: 23049538
references.citation: J Gastroenterol. 2014 May;49(5):853-63
references.pmid: 23771433
references.citation: Antioxid Redox Signal. 2013 Feb 10;18(5):522-55
references.pmid: 22667998
references.citation: Structure. 2008 Nov 12;16(11):1714-23
references.pmid: 19000823
references.citation: PPAR Res. 2008;2008:326915
references.pmid: 18615182
references.citation: Cancer Lett. 2015 Nov 1;368(1):88-96
references.pmid: 26254540
references.citation: Toxicol Appl Pharmacol. 2012 Sep 1;263(2):225-32
references.pmid: 22750490
references.citation: PPAR Res. 2012;2012:560846
references.pmid: 23028383
references.citation: J Recept Signal Transduct Res. 2013;33(1):14-27
references.pmid: 23327583
references.citation: Nat Rev Drug Discov. 2013 Dec;12(12):931-47
references.pmid: 24287781
references.citation: J Cell Physiol. 2002 Jul;192(1):1-15
references.pmid: 12115731
references.citation: Gut. 2006 Jan;55(1):115-22
references.pmid: 16118353
references.citation: J Biol Chem. 2013 Jul 5;288(27):19484-502
references.pmid: 23687300
references.citation: J Neurosci. 2005 Aug 3;25(31):7101-10
references.pmid: 16079392
references.citation: Arch Toxicol. 2014 Feb;88(2):403-14
references.pmid: 24057571
references.citation: Sci Transl Med. 2015 May 27;7(289):289ra86
references.pmid: 26019222
references.citation: Br J Cancer. 2008 Aug 5;99(3):464-72
references.pmid: 18648370
references.citation: Oncogene. 2014 Feb 27;33(9):1101-12
references.pmid: 23542179
references.citation: Cancer Res. 2015 Sep 15;75(18):3890-901
references.pmid: 26216549
references.citation: Carcinogenesis. 2000 Feb;21(2):139-46
references.pmid: 10657949
references.citation: Gut. 2004 Mar;53(3):331-8
references.pmid: 14960510
references.citation: Cancer Cell Int. 2015 Nov 05;15:106
references.pmid: 26549987
references.citation: Nature. 2011 Jul 14;475(7355):231-4
references.pmid: 21753854
references.citation: Biochem Pharmacol. 2014 Nov 1;92(1):90-101
references.pmid: 25078786
references.citation: Clin Cancer Res. 2009 Jul 15;15(14):4572-80
references.pmid: 19584167
references.citation: Mol Cancer. 2015;14:85
references.pmid: 25889730
references.citation: Carcinogenesis. 2005 Jan;26(1):65-72
references.pmid: 15358636
references.citation: World J Gastroenterol. 2003 Oct;9(10):2149-53
references.pmid: 14562367
references.citation: Cell Metab. 2014 Oct 7;20(4):650-61
references.pmid: 25264247
references.citation: Mol Cancer Res. 2010 Jun;8(6):821-32
references.pmid: 20530583
references.citation: Mol Aspects Med. 2009 Feb-Apr;30(1-2):1-12
references.pmid: 18796312
references.citation: Biochem J. 2014 Jun 15;460(3):425-35
references.pmid: 24707893
references.citation: Cancer Res. 2005 Feb 1;65(3):982-90
references.pmid: 15705899
references.citation: J Clin Invest. 2014 Jan;124(1):117-28
references.pmid: 24292713
references.citation: Cancer Chemother Pharmacol. 2014 Jan;73(1):97-102
references.pmid: 24146260
references.citation: Am J Pathol. 2010 Mar;176(3):1462-8
references.pmid: 20093479
references.citation: Am J Pathol. 2012 Oct;181(4):1316-26
references.pmid: 22998775
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12098-102
references.pmid: 16880406
references.citation: Cell Signal. 2007 Sep;19(9):1807-19
references.pmid: 17570640
references.citation: Exp Eye Res. 2011 Mar;92(3):162-3
references.pmid: 20488177
references.citation: J Hematol Oncol. 2014;7:30
references.pmid: 24708874
references.citation: J Pharmacol Sci. 2004 Oct;96(2):134-43
references.pmid: 15492468
references.citation: Carcinogenesis. 2011 Feb;32(2):190-6
references.pmid: 21047993
references.citation: Exp Cell Res. 2003 Sep 10;289(1):143-51
references.pmid: 12941612
references.citation: J Lipid Res. 2002 Nov;43(11):1818-28
references.pmid: 12401880
references.citation: Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):8070-5
references.pmid: 26080408
references.citation: Mol Cell Biol. 2014 Sep 15;34(18):3421-34
references.pmid: 25002527
references.citation: Mol Cell Biochem. 2015 Jul;405(1-2):205-21
references.pmid: 25896132
references.citation: Mol Cancer Ther. 2003 Jan;2(1):1-7
references.pmid: 12533667
references.citation: Pancreas. 2010 Apr;39(3):332-9
references.pmid: 19820419
references.citation: Curr Oncol. 2010 Jun;17(3):9-16
references.pmid: 20567622
references.citation: J Oncol. 2009;2009:519563
references.pmid: 19746172
references.citation: Nat Rev Drug Discov. 2009 Jul;8(7):579-91
references.pmid: 19478820
references.citation: Cancer Metastasis Rev. 2007 Dec;26(3-4):525-34
references.pmid: 17763971
references.citation: Anticancer Drugs. 2007 Jan;18(1):65-78
references.pmid: 17159504
references.citation: J Biol Chem. 2007 Jun 22;282(25):18162-72
references.pmid: 17449869
references.citation: Int J Oncol. 2015 Jan;46(1):175-84
references.pmid: 25333644
references.citation: PPAR Res. 2012;2012:461784
references.pmid: 22919364
references.citation: World J Gastroenterol. 2014 Jun 21;20(23):7137-51
references.pmid: 24966585
references.citation: J Biol Chem. 2010 Aug 20;285(34):26358-68
references.pmid: 20566639
references.citation: Cancer Cell. 2011 Mar 8;19(3):387-400
references.pmid: 21397861
references.citation: Antioxid Redox Signal. 2013 Aug 10;19(5):465-81
references.pmid: 23145493
references.citation: Nature. 2011 Jul 7;475(7354):106-9
references.pmid: 21734707
references.citation: J Biol Chem. 2001 Oct 12;276(41):38152-8
references.pmid: 11477100
references.citation: Cancer Lett. 2011 Dec 15;312(1):55-61
references.pmid: 21906871
references.citation: Oncogene. 2014 Mar 6;33(10):1265-73
references.pmid: 23524582
references.citation: Clin Cancer Res. 2006 Nov 1;12(21):6444-51
references.pmid: 17085658
references.citation: Cell Signal. 2012 Jun;24(6):1229-40
references.pmid: 22360859