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BMC Cancer
Published in: BMC Cancer 1/2011

Open Access 01-12-2011 | Research article

ER stress drives Lipocalin 2 upregulation in prostate cancer cells in an NF-κB-dependent manner

Authors: Navin R Mahadevan, Jeffrey Rodvold, Gonzalo Almanza, Antonio Fernández Pérez, Matthew C Wheeler, Maurizio Zanetti

Published in: BMC Cancer | Issue 1/2011

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Abstract

Background

Tumor cells adapt to endoplasmic reticulum (ER) stress through a set of conserved intracellular pathways, as part of a process termed the unfolded protein response (UPR). The expression of UPR genes/proteins correlates with increasing progression and poor clinical outcome of several tumor types, including prostate cancer. UPR signaling can activate NF-κB, a master regulator of transcription of pro-inflammatory, tumorigenic cytokines. Previous studies have shown that Lipocalin 2 (Lcn2) is upregulated in several epithelial cancers, including prostate cancer, and recently Lcn2 was implicated as a key mediator of breast cancer progression. Here, we hypothesize that the tumor cell UPR regulates Lcn2 production.

Methods

We interrogated Lcn2 regulation in murine and human prostate cancer cells undergoing pharmacological and physiological ER stress, and tested UPR and NF-κB dependence by using pharmacological inhibitors of these signaling pathways.

Results

Induction of ER stress using thapsigargin (Tg), a canonical pharmacologic ER stress inducer, or via glucose deprivation, a physiologic ER stressor present in the tumor microenvironment, upregulates LCN2 production in murine and human prostate cancer cells. Inhibition of the UPR using 4-phenylbutyric acid (PBA) dramatically decreases Lcn2 transcription and translation. Inhibition of NF-κB in prostate cancer cells undergoing Tg-mediated ER stress by BAY 11-7082 abrogates Lcn2 upregulation.

Conclusions

We conclude that the UPR activates Lcn2 production in prostate cancer cells in an NF-κB-dependent manner. Our results imply that the observed upregulation of Lipocalin 2 in various types of cancer cells may be the direct consequence of concomitant UPR activation, and that the ER stress/Lipocalin 2 axis is a potential new target for intervention in cancer progression.
Appendix
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Literature
1.
Yang J, Bielenberg DR, Rodig SJ, Doiron R, Clifton MC, Kung AL, Strong RK, Zurakowski D, Moses MA: Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci USA. 2009, 106 (10): 3913-3918. 10.1073/pnas.0810617106.CrossRefPubMedPubMedCentral
2.
Leng X, Ding T, Lin H, Wang Y, Hu L, Hu J, Feig B, Zhang W, Pusztai L, Symmans WF, Wu Y, Arlinghaus RB: Inhibition of lipocalin 2 impairs breast tumorigenesis and metastasis. Cancer Res. 2009, 69 (22): 8579-8584. 10.1158/0008-5472.CAN-09-1934.CrossRefPubMed
3.
Berger T, Cheung CC, Elia AJ, Mak TW: Disruption of the Lcn2 gene in mice suppresses primary mammary tumor formation but does not decrease lung metastasis. Proc Natl Acad Sci USA. 2010, 107 (7): 2995-3000. 10.1073/pnas.1000101107.CrossRefPubMedPubMedCentral
4.
Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N: Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem. 1993, 268 (14): 10425-10432.PubMed
5.
Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK: The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell. 2002, 10 (5): 1033-1043. 10.1016/S1097-2765(02)00708-6.CrossRefPubMed
6.
Bao G, Clifton M, Hoette TM, Mori K, Deng SX, Qiu A, Viltard M, Williams D, Paragas N, Leete T, Kulkarni R, Li X, Lee B, Kalandadze A, Ratner AJ, Pizarro JC, Schmidt-Ott KM, Landry DW, Raymond KN, Strong RK, Barasch J: Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex. Nat Chem Biol. 2010, 6 (8): 602-609.CrossRefPubMedPubMedCentral
7.
Devireddy LR, Hart DO, Goetz DH, Green MR: A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell. 141 (6): 1006-1017.
8.
Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J: An iron delivery pathway mediated by a lipocalin. Mol Cell. 2002, 10 (5): 1045-1056. 10.1016/S1097-2765(02)00710-4.CrossRefPubMed
9.
Xu S, Venge P: Lipocalins as biochemical markers of disease. Biochim Biophys Acta. 2000, 1482 (1-2): 298-307. 10.1016/S0167-4838(00)00163-1.CrossRefPubMed
10.
Iannetti A, Pacifico F, Acquaviva R, Lavorgna A, Crescenzi E, Vascotto C, Tell G, Salzano AM, Scaloni A, Vuttariello E, Chiappetta G, Formisano S, Leonardi A: The neutrophil gelatinase-associated lipocalin (NGAL), a NF-kappaB-regulated gene, is a survival factor for thyroid neoplastic cells. Proc Natl Acad Sci USA. 2008, 105 (37): 14058-14063. 10.1073/pnas.0710846105.CrossRefPubMedPubMedCentral
11.
Li SH, Hawthorne VS, Neal CL, Sanghera S, Xu J, Yang J, Guo H, Steeg PS, Yu D: Upregulation of neutrophil gelatinase-associated lipocalin by ErbB2 through nuclear factor-kappaB activation. Cancer Res. 2009, 69 (24): 9163-9168. 10.1158/0008-5472.CAN-09-2483.CrossRefPubMedPubMedCentral
12.
Ma Y, Hendershot LM: The role of the unfolded protein response in tumour development: friend or foe?. Nat Rev Cancer. 2004, 4 (12): 966-977. 10.1038/nrc1505.CrossRefPubMed
13.
Harding HP, Calfon M, Urano F, Novoa I, Ron D: Transcriptional and translational control in the Mammalian unfolded protein response. Annu Rev Cell Dev Biol. 2002, 18: 575-599. 10.1146/annurev.cellbio.18.011402.160624.CrossRefPubMed
14.
15.
Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ: Cancer statistics, 2004. CA Cancer J Clin. 2004, 54 (1): 8-29. 10.3322/canjclin.54.1.8.CrossRefPubMed
16.
Fu Y, Wey S, Wang M, Ye R, Liao CP, Roy-Burman P, Lee AS: Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium. Proc Natl Acad Sci USA. 2008, 105 (49): 19444-19449. 10.1073/pnas.0807691105.CrossRefPubMedPubMedCentral
17.
Daneshmand S, Quek ML, Lin E, Lee C, Cote RJ, Hawes D, Cai J, Groshen S, Lieskovsky G, Skinner DG, Lee AS, Pinski J: Glucose-regulated protein GRP78 is up-regulated in prostate cancer and correlates with recurrence and survival. Hum Pathol. 2007, 38 (10): 1547-1552. 10.1016/j.humpath.2007.03.014.CrossRefPubMed
18.
Roy R, Louis G, Loughlin KR, Wiederschain D, Kilroy SM, Lamb CC, Zurakowski D, Moses MA: Tumor-specific urinary matrix metalloproteinase fingerprinting: identification of high molecular weight urinary matrix metalloproteinase species. Clin Cancer Res. 2008, 14 (20): 6610-6617. 10.1158/1078-0432.CCR-08-1136.CrossRefPubMedPubMedCentral
19.
Wheeler MC, Rizzi M, Sasik R, Almanza G, Hardiman G, Zanetti M: KDEL-Retained Antigen in B Lymphocytes Induces a Proinflammatory Response: A Possible Role for Endoplasmic Reticulum Stress in Adaptive T Cell Immunity. J Immunol. 2008, 181 (1): 256-264.CrossRefPubMed
20.
Greenberg NM, DeMayo F, Finegold MJ, Medina D, Tilley WD, Aspinall JO, Cunha GR, Donjacour AA, Matusik RJ, Rosen JM: Prostate cancer in a transgenic mouse. Proceedings of the National Academy of Sciences of the United States of America. 1995, 92 (8): 3439-3443. 10.1073/pnas.92.8.3439.CrossRefPubMedPubMedCentral
21.
Hurwitz AA, Foster BA, Allison JP, Greenberg NM, Kwon ED: The TRAMP mouse as a model for prostate cancer. Curr Protoc Immunol. 2001, Chapter 20: Unit 20 25
22.
Stathopoulos GT, Zhu Z, Everhart MB, Kalomenidis I, Lawson WE, Bilaceroglu S, Peterson TE, Mitchell D, Yull FE, Light RW, Blackwell TS: Nuclear factor-kappaB affects tumor progression in a mouse model of malignant pleural effusion. Am J Respir Cell Mol Biol. 2006, 34 (2): 142-150. 10.1165/rcmb.2005-0130OC.CrossRefPubMed
23.
Hung JH, Su IJ, Lei HY, Wang HC, Lin WC, Chang WT, Huang W, Chang WC, Chang YS, Chen CC, Lai MD: Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-kappaB and pp38 mitogen-activated protein kinase. J Biol Chem. 2004, 279 (45): 46384-46392. 10.1074/jbc.M403568200.CrossRefPubMed
24.
Kaneko M, Niinuma Y, Nomura Y: Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2. Biol Pharm Bull. 2003, 26 (7): 931-935. 10.1248/bpb.26.931.CrossRefPubMed
25.
Grivennikov S, Karin M: Autocrine IL-6 signaling: a key event in tumorigenesis?. Cancer Cell. 2008, 13 (1): 7-9. 10.1016/j.ccr.2007.12.020.CrossRefPubMed
26.
Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M: IL-23 promotes tumour incidence and growth. Nature. 2006, 442 (7101): 461-465. 10.1038/nature04808.CrossRefPubMed
27.
Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS: Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006, 313 (5790): 1137-1140. 10.1126/science.1128294.CrossRefPubMedPubMedCentral
28.
Pierce JW, Schoenleber R, Jesmok G, Best J, Moore SA, Collins T, Gerritsen ME: Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. J Biol Chem. 1997, 272 (34): 21096-21103. 10.1074/jbc.272.34.21096.CrossRefPubMed
29.
Cooper GM: Oncogenes. 1990, Boston MA: Jones and Bartlett Publishers Inc., 1
30.
Flowers MT, Keller MP, Choi Y, Lan H, Kendziorski C, Ntambi JM, Attie AD: Liver gene expression analysis reveals endoplasmic reticulum stress and metabolic dysfunction in SCD1-deficient mice fed a very low-fat diet. Physiol Genomics. 2008, 33 (3): 361-372. 10.1152/physiolgenomics.00139.2007.CrossRefPubMed
31.
Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N, Harding HP, Ron D: Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol. 2004, 24 (23): 10161-10168. 10.1128/MCB.24.23.10161-10168.2004.CrossRefPubMedPubMedCentral
32.
Shen F, Hu Z, Goswami J, Gaffen SL: Identification of common transcriptional regulatory elements in interleukin-17 target genes. J Biol Chem. 2006, 281 (34): 24138-24148. 10.1074/jbc.M604597200.CrossRefPubMed
33.
Dong D, Ni M, Li J, Xiong S, Ye W, Virrey JJ, Mao C, Ye R, Wang M, Pen L, Dubeau L, Groshen S, Hofman FM, Lee AS: Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res. 2008, 68 (2): 498-505. 10.1158/0008-5472.CAN-07-2950.CrossRefPubMed
34.
Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh RJ, Bell J, Ron D, Wouters BG, Koumenis C: ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 2005, 24 (19): 3470-3481. 10.1038/sj.emboj.7600777.CrossRefPubMedPubMedCentral
35.
Zhuang L, Scolyer RA, Lee CS, McCarthy SW, Cooper WA, Zhang XD, Thompson JF, Hersey P: Expression of glucose-regulated stress protein GRP78 is related to progression of melanoma. Histopathology. 2009, 54 (4): 462-470. 10.1111/j.1365-2559.2009.03242.x.CrossRefPubMed
36.
Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, et al: Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005, 310 (5748): 644-648. 10.1126/science.1117679.CrossRefPubMed
37.
Lee AS: GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 2007, 67 (8): 3496-3499. 10.1158/0008-5472.CAN-07-0325.CrossRefPubMed
Metadata
Title
ER stress drives Lipocalin 2 upregulation in prostate cancer cells in an NF-κB-dependent manner
Authors
Navin R Mahadevan
Jeffrey Rodvold
Gonzalo Almanza
Antonio Fernández Pérez
Matthew C Wheeler
Maurizio Zanetti
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2011
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-11-229

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