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Open Access 01-12-2011 | Research

Clusterin confers gmcitabine resistance in pancreatic cancer

Authors: Qingfeng Chen, Zhengkun Wang, Kejun Zhang, Xiaoyi Liu, Weihong Cao, Lei Zhang, Shuhua Zhang, Bomin Yan, Yaoguang Wang, Chunping Xia

Published in: World Journal of Surgical Oncology | Issue 1/2011

Abstract

Objective

To measure clusterin expression in pancreatic cancer tissues and cell lines and to evaluate whether clusterin confers resistance to gmcitabine in pancreatic cancer cells.

Methods

Immunohistochemistry for clusterin was performed on 50 primary pancreatic cancer tissues and 25 matched backgrounds, and clusterin expression in 5 pancreatic cancer cell lines was quantified by Western blot and PT-PCR. The correlation between clusterin expression level and gmcitabine IC50 in pancreatic cancer cell lines was evaluated. The effect of an antisense oligonucleotide (ASO) against clusterin(OGX-011) on gmcitabine resistance was evaluated by MTT assays. Xenograft model was used to demonstrate tumor growth.

Results

Pancreatic cancer tissues expressed significantly higher levels of clusterin than did normal pancreatic tissues (P < 0.01). Clusterin expression levels were correlated with gmcitabine resistance in pancreatic cancer cell lines, and OGX-011 significantly decreased BxPc-3 cells resistance to gmcitabine (P < 0.01). In vivo systemic administration of AS clusterin and gmcitabine significantly decreased the s.c. BxPC-3 tumor volume compared with mismatch control ODN plus gmcitabine.

Conclusion

Our finding that clusterin expression was significantly higher in pancreatic cancer than in normal pancreatic tissues suggests that clusterin may confer gmcitabine resistance in pancreatic cancer cells.

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Arlt A, Gehrz A, Müerköster S, Vorndamm J, Kruse ML, Fölsch UR, Schäfer H: Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gmcitabine-induced cell death. Oncogene. 2003, 22: 3243-51. 10.1038/sj.onc.1206390.CrossRefPubMed

Rosenberg ME, Silkensen J: Clusterin: Physiologic and pathophysiologic considerations. Int J Biochem Cell Biol. 1995, 27: 633-645. 10.1016/1357-2725(95)00027-M.CrossRefPubMed

Kyprianou N, English HF, Davison NE, Issac JT: Programmed cell death during regression of the MCF-7 human breast cancer following estrogen ablation. Cancer Res. 1991, 51: 162-166.PubMed

Wright PS, Cross-Doersen D, Th'ng JP, Guo XW, Crissman HA, Bradbury EM, Montgomery LR: A ribonucleotide reductase inhibitor, MDL 101, 731, induces apoptosis and elevates TRPM-2 mRNA levels in human prostate tumor xenografts. Exp Cell Res. 1996, 222: 54-60. 10.1006/excr.1996.0007.CrossRefPubMed

Schwochau GB, Nath KA, Rosenberg ME: Clusterin protects against oxidative stress in vitro through aggressive and nonaggressive properties. Kidney Int. 1998, 53: 1647-1653. 10.1046/j.1523-1755.1998.00902.x.CrossRefPubMed

Savković V, Gantzer H, Reiser U: Clusterin is protective in pancreatitis through anti-apoptotic and anti-inflammatory properties. Biochem Biophys Res Commun. 2007, 356: 431-7. 10.1016/j.bbrc.2007.02.148.CrossRefPubMed

Miyake H, Gleave M, Kamidono S, Hara I: Overexpression of clusterin in transitional cell carcinoma of the bladder is related to disease progression and recurrence. Urology. 2002, 59: 150-4. 10.1016/S0090-4295(01)01484-4.CrossRefPubMed

Lourda M, Trougakos IP, Gonos ES: Development of resistance to chemotherapeutic drugs in human osteosarcoma cell lines largely depends on up-regulation of Clusterin/Apolipoprotein. J Int J Cancer. 2007, 12: 611-22.CrossRef

Redondo M, Villar E, Torres-Munoz J, Tellez T, Morell M, Petito CK: Overexpression of clusterin in human breast carcinoma. Am J Pathol. 2000, 157: 393-399. 10.1016/S0002-9440(10)64552-X.PubMedCentralCrossRefPubMed

10.

Miyake H, Gleave ME, Arakawa S, Kamidomi S, Hara I: Introducing the clusterin gene into human renal cell carcinoma cells enhances their metastatic potentials. J Urol. 2002, 167: 2003-2008.

11.

Trougakos IP, So A, Jansen B, Gleave ME, Gonos ES: Silencing expression of the clusterin/apolipoprotein j gene in human cancer cells using small interfering RNA induces spontaneous apoptosis, reduced growth ability, and cell sensitization to genotoxic and oxidative stress. Cancer Res. 2004, 64: 1834-42. 10.1158/0008-5472.CAN-03-2664.CrossRefPubMed

12.

Chung J, Kwak C, Jin RJ, Lee CH, Lee KH, Lee SE: Enhanced chemosensitivity of bladder cancer cells to cisplatin by suppression of clusterin in vitro. Cancer Lett. 2004, 203: 155-61. 10.1016/j.canlet.2003.07.008.CrossRefPubMed

13.

Miyake H, Eto H, Hara I, So A, Li D, Gleave ME: Synergistic antitumor activity by combined treatment with gmcitabine and antisense oligodeoxynucleotide targeting clusterin gene in an intravesical administration model against human bladder cancer kotcc-1 cells. J Urol. 2004, 171: 2477-81. 10.1097/01.ju.0000118382.89456.f7.CrossRefPubMed

14.

Muramaki M, So A, Hayashi N, Sowery R, Miyake H, Fujisawa M, Gleave ME: Chemosensitization of gmcitabine-resistant human bladder cancer cell line both in vitro and in vivo using antisense oligonucleotide targeting the anti-apoptotic gene, clusterin. BJU Int. 2009, 103: 384-90. 10.1111/j.1464-410X.2008.08098.x.CrossRefPubMed

15.

Djeu JY, Wei S: Clusterin and chemoresistance. Adv Cancer Res. 2009, 105: 77-92.PubMedCentralCrossRefPubMed

16.

Zhang K, Dong Chen, Jiao X: Slug enhances invasion ability of pancreatic cancer cells through upregulation of matrix metalloproteinase-9 and actin cytoskeleton remodeling. Laboratory Investigation. 2011, 1-13.

17.

Fritz IB, Burdzy K, Setchell B, Blaschuk O: Ram rete testis fluid contains a protein (clusterin) which influences cell-cell interactions in vitro. Biol Reprod. 1983, 28: 1173-1188. 10.1095/biolreprod28.5.1173.CrossRefPubMed

18.

Trougakos IP, Gonos ES: Clusterin/apolipoprotein J in human aging and cancer. Int J Biochem Cell Biol. 2002, 34: 1430-1448. 10.1016/S1357-2725(02)00041-9.CrossRefPubMed

19.

Shannan B, Seifert M, Leskov K, Willis J, Boothman D, Tilgen W, Reichrath J: Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer. Cell Death Differ. 2006, 13: 12-19. 10.1038/sj.cdd.4401779.CrossRefPubMed

20.

Zhang H, Kim JK, Edwards CA, Xu Z, Taichman R, Wang CY: Clusterin inhibits apoptosis by interacting with activated Bax. Nat Cell Biol. 2005, 7: 909-915. 10.1038/ncb1291.CrossRefPubMed

21.

Leskov KS, Klokov DY, Li J, Kinsella TJ, Boothman DA: Synthesis and functional analyses of nuclear clusterin, a cell death protein. J Biol Chem. 2003, 278: 11590-11600. 10.1074/jbc.M209233200.CrossRefPubMed

22.

Sowery RD, Hadaschik BA, So AI, Zoubeidi A, Fazli L, Hurtado-Coll A, Gleave ME: Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy. BJU Int. 2008, 102: 389-97. 10.1111/j.1464-410X.2008.07618.x.CrossRefPubMed

23.

So A, Sinnemann S, Huntsman D, Fazli L, Gleave M: Knockdown of the cytoprotective chaperone, clusterin, chemosensitizes human breast cancer cells both in vitro and in vivo. Mol Cancer Ther. 2005, 4: 1837-49. 10.1158/1535-7163.MCT-05-0178.CrossRefPubMed

24.

July LV, Beraldi E, So A, Fazli L, Evans K, English JC, Gleave ME: Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells both in vitro and in vivo. Mol Cancer Ther. 2004, 3: 223-32.PubMed

25.

Zellweger T, Miyake H, July LV, Akbari M, Kiyama S, Gleave ME: Chemosensitization of human renal cell cancer using antisense oligonucleotides targeting the antiapoptotic gene clusterin. Neoplasia. 2001, 3: 360-7. 10.1038/sj.neo.7900174.PubMedCentralCrossRefPubMed

26.

Sheikh R, Walsh N, Clynes M, O'Connor R, McDermott R: Challenges of drug resistance in the management of pancreatic cancer. Expert Rev Anticancer Ther. 2010, 10: 1647-61. 10.1586/era.10.148.CrossRefPubMed

27.

Xie MJ, Motoo Y, Su SB, Mouri H, Ohtsubo K, Matsubara F, Sawabu N: Expression of clusterin in human pancreatic cancer. Pancreas. 2002, 25: 234-8. 10.1097/00006676-200210000-00004.CrossRefPubMed

Title: Clusterin confers gmcitabine resistance in pancreatic cancer
Authors: Qingfeng Chen
Zhengkun Wang
Kejun Zhang
Xiaoyi Liu
Weihong Cao
Lei Zhang
Shuhua Zhang
Bomin Yan
Yaoguang Wang
Chunping Xia
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: World Journal of Surgical Oncology / Issue 1/2011
Electronic ISSN: 1477-7819
DOI: https://doi.org/10.1186/1477-7819-9-59

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Clusterin confers gmcitabine resistance in pancreatic cancer

Abstract

Objective

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objective

Methods

Results

Conclusion

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