Restricted accessResearch articleFirst published online 2013-07
Expression of the Endoplasmic Reticulum Oxidoreductase Ero1α in Gastro-Intestinal Cancer Reveals a Link Between Homocysteine and Oxidative Protein Folding
Aim: Ero proteins are central to oxidative protein folding in the endoplasmic reticulum (ER), but their expression varies in a tissue-specific manner. The aim of this work was to establish the expression of Ero1α in the digestive system and to examine the behavior of Ero1α in premalignant Barrett's esophagus, esophageal (OE) and gastric cancers and esophageal cancer cell lines. Results: Ero1α is expressed in the columnar epithelium of Barrett's tissue, and in OE tumors and gastric tumors. Homocysteine, a precursor in the metabolism of cysteine and methionine, induces the active Ox1 form of Ero1α in the OE cancer cell line OE33. Innovation: These results demonstrate for the first time that Ero1α can sense the level of an amino acid precursor, identifying a potential link between diet, antioxidants, and oxidative protein folding in the ER. Conclusion: The high expression of Ero1α in cancers of the esophagus and stomach demonstrates the importance of ER redox regulation in the gastro-intestinal (GI) tract in health and disease. Proteins and metabolites involved in disulfide bond formation and redox regulation may be suitable targets for both biomarker and drug development in GI cancer. Antioxid. Redox Signal. 19, 24–35.
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References
1.
Appenzeller-HerzogC. Glutathione- and non-glutathione-based oxidant control in the endoplasmic reticulum. J Cell Sci, 124:847–855. 2011.
2.
Appenzeller-HerzogC, RiemerJ, ChristensenB, SorensenES, EllgaardL. A novel disulphide switch mechanism in Ero1alpha balances ER oxidation in human cells. EMBO J, 27:2977–2987. 2008.
3.
BakerKM, ChakravarthiS, LangtonKP, SheppardAM, LuH, BulleidNJ. Low reduction potential of Ero1alpha regulatory disulphides ensures tight control of substrate oxidation. EMBO J, 27:2988–2997. 2008.
4.
BenhamAM, CabibboA, FassioA, BulleidN, SitiaR, BraakmanI. The CXXCXXC motif determines the folding, structure and stability of human Ero1-Lalpha. EMBO J, 19:4493–4502. 2000.
5.
BraakmanI, BulleidNJ. Protein folding and modification in the mammalian endoplasmic reticulum. Annu Rev Biochem, 80:71–99. 2011.
6.
BrychtovaV, VojtesekB, HrstkaR. Anterior gradient 2: a novel player in tumor cell biology. Cancer Lett, 304:1–7. 2011.
7.
ChenD, JinK, KawaguchiK, NakayamaM, ZhouX, XiongZ, ZhouA, MaoXO, GreenbergDA, GrahamSH, SimonRP. Ero1-L, an ischemia-inducible gene from rat brain with homology to global ischemia-induced gene 11 (Giig11), is localized to neuronal dendrites by a dispersed identifier (ID) element-dependent mechanism. J Neurochem, 85:670–679. 2003.
8.
ChinKT, KangG, QuJ, GardnerLB, CoetzeeWA, ZitoE, FishmanGI, RonD. The sarcoplasmic reticulum luminal thiol oxidase ERO1 regulates cardiomyocyte excitation-coupled calcium release and response to hemodynamic load. FASEB J, 25:2583–2591. 2011.
9.
Di BuonoM, WykesLJ, ColeDE, BallRO, PencharzPB. Regulation of sulfur amino acid metabolism in men in response to changes in sulfur amino acid intakes. J Nutr, 133:733–739. 2003.
10.
Dias-GunasekaraS, GubbensJ, van LithM, DunneC, WilliamsJA, KatakyR, ScoonesD, LapthornA, BulleidNJ, BenhamAM. Tissue-specific expression and dimerization of the endoplasmic reticulum oxidoreductase Ero1beta. J Biol Chem, 280:33066–33075. 2005.
11.
EnzingerPC, MayerRJ. Esophageal cancer. N Engl J Med, 349:2241–2252. 2003.
FeigeMJ, HendershotLM. Disulfide bonds in ER protein folding and homeostasis. Curr Opin Cell Biol, 23:167–175. 2011.
14.
FernandesDC, ManoelAH, WosniakJJr., LaurindoFR. Protein disulfide isomerase overexpression in vascular smooth muscle cells induces spontaneous preemptive NADPH oxidase activation and Nox1 mRNA expression: effects of nitrosothiol exposure. Arch Biochem Biophys, 484:197–204. 2009.
15.
GessB, HofbauerKH, WengerRH, LohausC, MeyerHE, KurtzA. The cellular oxygen tension regulates expression of the endoplasmic oxidoreductase ERO1-Lalpha. Eur J Biochem, 270:2228–2235. 2003.
16.
HagiwaraM, MaegawaK, SuzukiM, UshiodaR, ArakiK, MatsumotoY, HosekiJ, NagataK, InabaK. Structural basis of an ERAD pathway mediated by the ER-resident protein disulfide reductase ERdj5. Mol Cell, 41:432–444. 2011.
17.
HatahetF, RuddockLW. Protein disulfide isomerase: a critical evaluation of its function in disulfide bond formation. Antioxid Redox Signal, 11:2807–2850. 2009.
18.
KimS, SiderisDP, SevierCS, KaiserCA. Balanced Ero1 activation and inactivation establishes ER redox homeostasis. J Cell Biol, 196:713–725. 2012.
19.
KyrgidisA, KountourasJ, ZavosC, ChatzopoulosD. New molecular concepts of Barrett's esophagus: clinical implications and biomarkers. J Surg Res, 125:189–212. 2005.
20.
LiG, ScullC, OzcanL, TabasI. NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis. J Cell Biol, 191:1113–1125. 2010.
21.
MayD, ItinA, GalO, KalinskiH, FeinsteinE, KeshetE. Ero1-L alpha plays a key role in a HIF-1-mediated pathway to improve disulfide bond formation and VEGF secretion under hypoxia: implication for cancer. Oncogene, 24:1011–1020. 2005.
22.
MezghraniA, FassioA, BenhamA, SimmenT, BraakmanI, SitiaR. Manipulation of oxidative protein folding and PDI redox state in mammalian cells. EMBO J, 20:6288–6296. 2001.
23.
Navarro SilveraSA, MayneST, RischH, GammonMD, VaughanTL, ChowWH, DubrowR, SchoenbergJB, StanfordJL, WestAB, RotterdamH, BlotWJ, FraumeniJFJr.Food group intake and risk of subtypes of esophageal and gastric cancer. Int J Cancer, 123:852–860. 2008.
24.
NemotoT, SatoN, IwanariH, YamashitaH, TakagiT. Domain structures and immunogenic regions of the 90-kDa heat-shock protein (HSP90). Probing with a library of anti-HSP90 monoclonal antibodies and limited proteolysis. J Biol Chem, 272:26179–26187. 1997.
25.
NguyenVD, SaaranenMJ, KaralaAR, LappiAK, WangL, RaykhelIB, AlanenHI, SaloKE, WangCC, RuddockLW. Two endoplasmic reticulum PDI peroxidases increase the efficiency of the use of peroxide during disulfide bond formation. J Mol Biol, 406:503–515. 2011.
26.
OngCA, Lao-SirieixP, FitzgeraldRC. Biomarkers in Barrett's esophagus and esophageal adenocarcinoma: predictors of progression and prognosis. World J Gastroenterol, 16:5669–5681. 2010.
27.
OutinenPA, SoodSK, PfeiferSI, PamidiS, PodorTJ, LiJ, WeitzJI, AustinRC. Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood, 94:959–967. 1999.
28.
PaganiM, FabbriM, BenedettiC, FassioA, PilatiS, BulleidNJ, CabibboA, SitiaR. Endoplasmic reticulum oxidoreductin 1-lbeta (ERO1-Lbeta), a human gene induced in the course of the unfolded protein response. J Biol Chem, 275:23685–23692. 2000.
PappE, NardaiG, MandlJ, BanhegyiG, CsermelyP. FAD oxidizes the ERO1-PDI electron transfer chain: the role of membrane integrity. Biochem Biophys Res Commun, 338:938–945. 2005.
31.
ParkSW, ZhenG, VerhaegheC, NakagamiY, NguyenvuLT, BarczakAJ, KilleenN, ErleDJ. The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proc Natl Acad Sci U S A, 106:6950–6955. 2009.
32.
PerssonS, RosenquistM, KnoblachB, Khosravi-FarR, SommarinM, MichalakM. Diversity of the protein disulfide isomerase family: identification of breast tumor induced Hag2 and Hag3 as novel members of the protein family. Mol Phylogenet Evol, 36:734–740. 2005.
QiangL, WangH, FarmerSR. Adiponectin secretion is regulated by SIRT1 and the endoplasmic reticulum oxidoreductase Ero1-L alpha. Mol Cell Biol, 27:4698–4707. 2007.
37.
QuanteM, BhagatG, AbramsJA, MaracheF, GoodP, LeeMD, LeeY, FriedmanR, AsfahaS, DubeykovskayaZ, MahmoodU, FigueiredoJL, KitajewskiJ, ShawberC, LightdaleCJ, RustgiAK, WangTC. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell, 21:36–51. 2012.
38.
RockettJC, LarkinK, DarntonSJ, MorrisAG, MatthewsHR. Five newly established oesophageal carcinoma cell lines: phenotypic and immunological characterization. Br J Cancer, 75:258–263. 1997.
39.
RonzoniR, AnelliT, BrunatiM, CortiniM, FagioliC, SitiaR. Pathogenesis of ER storage disorders: modulating Russell body biogenesis by altering proximal and distal quality control. Traffic, 11:947–957. 2010.
40.
RuddockLW. Low-molecular-weight oxidants involved in disulfide bond formation. Antioxid Redox Signal, 16:1129–1138. 2012.
41.
SalekiK, HartiganN, LithM, BulleidN, BenhamAM. Differential oxidation of HLA-B2704 and HLA-B2705 in lymphoblastoid and transfected adherent cells. Antioxid Redox Signal, 8:292–299. 2006.
42.
SelhubJ. Homocysteine metabolism. Annu Rev Nutr, 19:217–246. 1999.
43.
SevierCS, KaiserCA. Ero1 and redox homeostasis in the endoplasmic reticulum. Biochim Biophys Acta, 1783:549–556. 2008.
44.
SevierCS, QuH, HeldmanN, GrossE, FassD, KaiserCA. Modulation of cellular disulfide-bond formation and the ER redox environment by feedback regulation of Ero1. Cell, 129:333–344. 2007.
StipanukMH. Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Annu Rev Nutr, 24:539–577. 2004.
47.
TavenderTJ, BulleidNJ. Peroxiredoxin IV protects cells from oxidative stress by removing H2O2 produced during disulphide formation. J Cell Sci, 123:2672–2679. 2010.
48.
TavenderTJ, SpringateJJ, BulleidNJ. Recycling of peroxiredoxin IV provides a novel pathway for disulphide formation in the endoplasmic reticulum. EMBO J, 29:4185–4197. 2010.
49.
TrachoothamD, AlexandreJ, HuangP. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?Nat Rev Drug Discov, 8:579–591. 2009.
50.
TranTM, IvanyiP, HilgertI, BrdickaT, PlaM, BreurB, FliegerM, IvaskovaE, HorejsiV. The epitope recognized by pan-HLA class I-reactive monoclonal antibody W6/32 and its relationship to unusual stability of the HLA-B27/beta2-microglobulin complex. Immunogenetics, 53:440–446. 2001.
51.
Valladares-AyerbesM, Diaz-PradoS, ReboredoM, MedinaV, Iglesias-DiazP, Lorenzo-PatinoMJ, CampeloRG, HazM, SantamarinaI, Anton-AparicioLM. Bioinformatics approach to mRNA markers discovery for detection of circulating tumor cells in patients with gastrointestinal cancer. Cancer Detect Prev, 32:236–250. 2008.
52.
VarsanyiM, SzarkaA, PappE, MakaiD, NardaiG, FulceriR, CsermelyP, MandlJ, BenedettiA, BanhegyiG. FAD transport and FAD-dependent protein thiol oxidation in rat liver microsomes. J Biol Chem, 279:3370–3374. 2004.
53.
WangK, BodempudiV, LiuZ, Borrego-DiazE, YamoutpoorF, MeyerA, WooRA, PanW, DudekAZ, OlyaeeMS, EsfandyariT, FarassatiF. Inhibition of mesothelin as a novel strategy for targeting cancer cells. PLoS One, 7:e33214. 2012.
54.
WangL, ZhuL, WangCC. The endoplasmic reticulum sulfhydryl oxidase Ero1beta drives efficient oxidative protein folding with loose regulation. Biochem J, 434:113–121. 2011.
55.
WangX, OuyangH, YamamotoY, KumarPA, WeiTS, DagherR, VincentM, LuX, BellizziAM, HoKY, CrumCP, XianW, McKeonF. Residual embryonic cells as precursors of a Barrett's-like metaplasia. Cell, 145:1023–1035. 2011.
56.
WangZ, HaoY, LoweAW. The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation. Cancer Res, 68:492–497. 2008.
57.
WangZV, SchrawTD, KimJY, KhanT, RajalaMW, FollenziA, SchererPE. Secretion of the adipocyte-specific secretory protein adiponectin critically depends on thiol-mediated protein retention. Mol Cell Biol, 27:3716–3731. 2007.
58.
WooHA, YimSH, ShinDH, KangD, YuDY, RheeSG. Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. Cell, 140:517–528. 2010.
59.
ZhaoF, EdwardsR, DizonD, AfrasiabiK, MastroianniJR, GeyfmanM, OuelletteAJ, AndersenB, LipkinSM. Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2-/- mice. Dev Biol, 338:270–279. 2010.
ZitoE, MeloEP, YangY, WahlanderA, NeubertTA, RonD. Oxidative protein folding by an endoplasmic reticulum-localized peroxiredoxin. Mol Cell, 40:787–797. 2010.
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