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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2009

Open Access 01-12-2009 | Research

Lewis y antigen promotes the proliferation of ovarian carcinoma-derived RMG-I cells through the PI3K/Akt signaling pathway

Authors: Juanjuan Liu, Bei Lin, Yingying Hao, Yue Qi, Liancheng Zhu, Feifei Li, Dawo Liu, Jianping Cong, Shulan Zhang, Masao Iwamori

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2009

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Abstract

Background

Lewis y antigen is difucosylated oligosaccharide and is carried by glycoconjugates at cell surface. Elevated expression of Lewis y has been found in 75% of ovarian tumor, and the high expression level is correlated to the tumor's pathological staging and prognosis. This study was to investigate the effect and the possible mechanism of Lewis y on the proliferation of human ovarian cancer cells.

Methods

We constructed a plasmid encoding α1,2-fucosyltransferase (α1,2-FT) gene and then transfected it into ovarian carcinoma-derived RMG-I cells with lowest Lewis y antigen expression level. Effect of Lewis y on cell proliferation was assessed after transfection. Changes in cell survival and signal transduction were evaluated after α-L-fucosidase, anti-Lewis y antibody and phosphatidylinositol 3-kinase (PI3K) inhibitor treatment.

Results

Our results showed that the levels of α1,2-FT gene and Lewis y increased significantly after transfection. The cell proliferation of ovarian carcinoma-derived RMG-I cells sped up as the Lewis y antigen was increased. Both of α-L-fucosidase and anti-Lewis y antibody inhibited the cell proliferation. The phosphorylation level of Akt was apparently elevated in Lewis y-overexpressing cells and the inhibitor of PI3K, LY294002, dramatically inhibited the growth of Lewis y-overexpressing cells. In addition, the phosphorylation intensity and difference in phosphorylation intensity between cells with different expression of α1,2-FT were attenuated significantly by the monoantibody to Lewis y and by the PI3K inhibitor LY294002.

Conclusions

Increased expression of Lewis y antigen plays an important role in promoting cell proliferation through activating PI3K/Akt signaling pathway in ovarian carcinoma-derived RMG-I cells. Inhibition of Lewis y expression may provide a new therapeutic approach for Lewis y positive ovarian cancer.
Appendix
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Literature
1.
Kitamura K, Stockert E, Garin-Chesa P, Welt S, Llovd KO, Armour KL, Wallace TP, Harris WJ, Carr FJ, Old LJ: Specificity analysis of blood group Lewis-y {Le(y)} antibodies generatedagainst synthetic and natural Le(y) determinants. Proc Natl Acad Sci USA. 1994, 91: 12957-12961. 10.1073/pnas.91.26.12957.CrossRef
2.
Hokke CH, Neeleman AP, Koeleman CA, Eijnden van den DH: Identification of an alpha3-fucosyltransferase and a novel alpha2-fucosyltransferase activity in cercariae of the schistosome Trichobilharzia ocellata: biosynthesis of the Fucalpha1 → 2Fucalpha1 → 3[Gal(NAc)beta1 → 4]GlcNAc sequence. Glycobiology. 1998, 8: 393-406. 10.1093/glycob/8.4.393.CrossRef
3.
Dettke M, Pálfi G, Loibner H: Activation-dependent expression of the blood group-related Lewis Y antigen on peripheral blood granulocytes. J Leukoc Biol. 2000, 68: 511-514.
4.
Arai Y, Nishida M: Differential diagnosis between normal endometrium and endometrial hyperplasia with immunostaining cytology using anti-LeY monoclonal antibody. Int J Gynecol Cancer. 2003, 13: 42-46. 10.1046/j.1525-1438.2003.13009.x.CrossRef
5.
Madjd Z, Parsons T, Watson NF, Spendlove I, Ellis I, Durrant LG: High expression of Lewis y/b antigens is associated with decreased survival in lymph node negative breast carcinomas. Breast Cancer Res. 2005, 7: R780-R787. 10.1186/bcr1305.CrossRef
6.
Kim YS, Yuan M, Itzkowitz SH, Sun QB, Kaizu T, Palekar A, Trump BF, Hakomori S: Expression of LeY and extended LeY blood group-related antigens in human malignant, premalignant, and nonmalignant colonic tissues. Cancer Res. 1986, 46: 5985-5992.
7.
Yin BW, Finstad CL, Kitamura K, Federici MG, Welshinger M, Kudrvashov V, Hoskins WJ, Welt S, Lloyd KO: Serological and immunochemical analysis of Lewis y (Ley) blood group antigen expression in epithelial ovarian cancer. Int J Cancer. 1996, 65: 406-412. 10.1002/(SICI)1097-0215(19960208)65:4<406::AID-IJC2>3.0.CO;2-0.CrossRef
8.
Iwamori M, Tanaka K, Kubushiro K, Lin B, Kiguchi K, Ishiwata I, Tsukazaki K, Nozawa S: Alterations in the glyolipid composition and cellular properties of ovarian carcinoma-derived RMG-1 cells on transfection of the α1,2-fucosyltransferase gene. Cancer Sci. 2005, 96: 26-30.CrossRef
9.
Zhao Y, Lin B, Hao YY, Yan LM, Liu JJ, Zhu LC, Zhang SL: The effects of Lewis(y) antigen content on drug resistance to carboplatin in ovarian cancer line RMG-I. Prog Biochem Biophys. 2008, 35: 1175-1182.
10.
Hynes NE, MacDonald G: Erb receptors and signaling pathways in cancer. Curr Opin Cell Biol. 2009, 21: 185-193. 10.1016/j.ceb.2008.12.010.CrossRef
11.
Matsumoto A, Ichikawa T, Nakao K, Miyaaki H, Hirano K, Fujimito M, Akiyama M, Miuma S, Ozawa E, Shibata H, Takeshita S, Yamasaki H, Ikeda M, Kato N, Eguchi K: Interferon-alpha-induced mTOR activation is an anti-hepatitis C virus signal via the phosphatidylinositol 3-kinase-Akt-independent pathway. J Gastroenterol. 2009, 44: 856-863. 10.1007/s00535-009-0075-1.CrossRef
12.
Park S, Zhao D, Hatanpaa KJ, Mickey BE, Saha D, Boothman DA, Story MD, Wong ET, Burma S, Georgescu MM, Rangenkar VM, Chauncey SS, Habib AA: RIP1 activates PI3K-Akt via a dual mechanism involving NF-kappaB-mediated inhibition of the mTOR-S6K-IRS1 negative feedback loop and down-regulation of PTEN. Cancer Res. 2009, 69: 4107-4111. 10.1158/0008-5472.CAN-09-0474.CrossRef
13.
Djerf EA, Trinks C, Abdiu A, Thunell LK, Hallbeck AL, Walz TM: ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839). Melanoma Res. 2009, 19: 156-166. 10.1097/CMR.0b013e32832c6339.CrossRef
14.
Basu A: Molecular targets of breast cancer: AKTing in concert. Breast Cancer. 2008, 2: 11-16.
15.
Dieterie A, Orth R, Daubrawa M, Grotemeier A, Alers S, Ullrich S, Lammers R, Wesselborg S, Stork B: The Akt inhibitor tricirbine sensitizes prostate carcinoma cells to TRAIL-induced apoptosis. Int J Cancer. 2009, 125: 932-941. 10.1002/ijc.24374.CrossRef
16.
Zhu K, Amin MA, Zha YY, Harlow LA, Koch AE: Mechanism by which H-2 g, a glucose analog of blood group H antigen, mediates angiogenesis. Blood. 2005, 105: 2343-2349. 10.1182/blood-2004-08-3140.CrossRef
17.
Sasak W, De Luca LM, Dion LD, Silverman-Jones CS: Effect of retionic acid on cell surface glycopeptides of cultured spontancously transformed mouse fibroblasts(BALB/c3T72-3 cells). Cancer Res. 1980, 40: 1944-1949.
18.
Prives C, Gottifredi V: The p21 and PCNA partnership: a new twist for an old plot. Cell Cycle. 2008, 7: 3840-3846.CrossRef
19.
Apweiler R, Hermjakob H, Sharon N: On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta. 1999, 1473: 4-8.CrossRef
20.
Narimatsu H: Human glycogene cloning: focus on beta 3-glycosyltransferase and beta 4-glycosyltransferase families. Curr Opin Struct Biol. 2006, 16: 567-575. 10.1016/j.sbi.2006.09.001.CrossRef
21.
Aamoudse CA, Bax M, Sánchez-Hernández M, García-Vallejo JJ, van Koovk Y: Glycan modification of the tumor antigen gp100 targets DC-SIGN to enhance dendritic cell induced antigen presentation to T cells. Int J Cancer. 2008, 122: 839-846. 10.1002/ijc.23101.CrossRef
22.
Nonaka M, Ma BY, Murai R, Nakamura N, Baba M, Kawasaki N, Hodohara K, Asano S: Glycosylation-Dependent Interactions of C-Type Lectin DC-SIGN with Colorectal Tumor-Associated Lewis Glycans Impair the Function and Differentiation of Monocyte-Derived Dendritic Cells. J Immunol. 2008, 180: 3347-3356.CrossRef
23.
Pai T, Chen Q, Zhang Y, Zolfaqhari R, Ross AC: Galactomutarotase and other galactose-related genes are rapidly induced by retinoic acid in human myeloid cells. Biochemistry. 2007, 46: 15198-151207. 10.1021/bi701891t.CrossRef
24.
Federici MF, Kudryashov V, Saigo PE, Finstad CL, Lloyd KO: Selection of carbohydrate antigens in human epithelial ovarian cancers as targets for immunotherapy: serous and mucinous tumors exhibit distinctive patterns of expression. Int J Cancer. 1999, 81: 193-198. 10.1002/(SICI)1097-0215(19990412)81:2<193::AID-IJC5>3.0.CO;2-S.CrossRef
25.
Zhu LC, Lin B, Hao YY, Li FF, Diao B, Zhang SL: Impact of alpha1,2-fucosyltransferase gene transfection on cancer related gene expression profile of human ovarian cancer cell line RMG-I. Ai Zheng. 2008, 27: 934-941.
26.
Klinger M, Farhan H, Just H, Drobny H, Himmler G, Loibner H, Mudde GC, Freissmuth M, Sexl V: Antibodies directed against Lewis-Y antigen inhibit signaling of Lewis-Y modified ErbB receptors. Cancer Res. 2004, 64: 1087-1093. 10.1158/0008-5472.CAN-03-2435.CrossRef
27.
Fraser M, Bai T, Tsang BK: Akt promotes cisplatin resistance in human ovarian cancer cells through inhibition of p53 phosphorylation and nuclear function. Int J Cancer. 2008, 22: 534-546. 10.1002/ijc.23086.CrossRef
28.
Kueck A, Opipari AW, Griffith KA, Tan L, Choi M, Huang J, Wahl H, Liu JR: Resveratrol inhibits glucose metabolism in human ovarian cancer cells. Gynecol Oncol. 2007, 103: 450-457. 10.1016/j.ygyno.2007.07.065.CrossRef
29.
Hemmings BA: Akt signaling: linking membrane events to life and death decisions. Science. 1997, 275: 628-630. 10.1126/science.275.5300.628.CrossRef
30.
Do TV, Kubba LA, Antenos M, Rademaker AW, Sturgis CD, Woodruff TK: The role of activin A and Akt/GSK signaling in ovarian tumor biology. Endocrinology. 2008, 149: 3809-3816. 10.1210/en.2007-1584.CrossRef
31.
Shtilbans V, Wu M, Burstein DE: Current overview of the role of Akt in cancer studies via applied immunohistochemistry. Ann Diagn Pathol. 2008, 12: 153-160. 10.1016/j.anndiagpath.2007.12.001.CrossRef
32.
Woenckhaus J, Steger K, Sturm K, Münstedt K, Franke FE, Fenic I: Prognostic value of PIK3CA and phosphorylated AKT expression in ovarian cancer. Virchows Arch. 2007, 450: 387-395. 10.1007/s00428-006-0358-3.CrossRef
33.
Azuma Y, Ito M, Taniguchi A, Matsumoto K: Expression of cell surface Lewis X and Y antigens and FUT mRNA is increased in Jurkat cells undergoing apoptosis. Biochim Biophys Acta. 2004, 1672: 157-163.CrossRef
34.
Inufusa H, Adachi T, Kivokawa T, Nakatani Y, Wakano T, Nakamura M, Okuno K, Shiozaki H, Yamamoto S, Suzuki M, Ando O, Kurimoto M, Miyake M, Yasutomi M: Ley glycolipid-recognizing monoclonal antibody inhibits procoagulant activity and metastasis of human adenocarcinoma. Int J Oncol. 2001, 19: 941-946.
35.
Cordel S, Goupille C, Hallouin E, Meflah K, Le Pendu J: Role for alpha1,2-fucosyltransferase and histo-blood group antigen H type 2 in resistance of rat colon carcinoma cells to 5-fluorouracil. Int J Cancer. 2000, 85: 142-148. 10.1002/(SICI)1097-0215(20000101)85:1<142::AID-IJC24>3.0.CO;2-K.CrossRef
36.
De Bolós C, Garrido M, Real FX: MUC6 apomucin shows a distinct normal tissue distribution that correlates with Lewis antigen expression in the human stomach. Gastroenterology. 1995, 109: 723-734. 10.1016/0016-5085(95)90379-8.CrossRef
37.
Basu A, Murthy U, Rodeck U, Herlyn M, Mattes L, Das M: Presence of tumor-associated antigens in epidermal growth factor receptors from different human carcinomas. Cancer Res. 1987, 47: 2531-2536.
38.
Wang XQ, Sun P, O'Gorman M, Tai T, Paller AS: Epidermal growth factor receptor glycosylation is required for ganglioside GM3 binding and GM3-mediated suppression [correction of suppression] of activation. Glycobiology. 2001, 11: 515-522. 10.1093/glycob/11.7.515.CrossRef
39.
Wang X, Zhang S, MacLennan GT, Eble JN, Lopez-Beltran A, Yang XJ, Pan CX, Zhou H, Montironi R, Cheng L: Epidermal growth factor receptor protein expression and gene amplification in small cell carcinoma of the urinary bladder. Clin Cancer Res. 2007, 13: 953-957. 10.1158/1078-0432.CCR-06-2167.CrossRef
40.
Guo P, Wang QY, Guo HB, Shen ZH, Chen HL: N-Acetylglucosaminyl-transferase V modifies the signaling pathway of epidermal growth factor receptor. Cell Mol Life Sci. 2004, 61: 1975-1804. 10.1007/s00018-004-4122-z.CrossRef
41.
Maines MD: Biliverdin reductase: PKC interaction at the cross-talk of MAPK and PI3K signaling pathways. Antioxid Redox Signal. 2007, 9: 2187-2195. 10.1089/ars.2007.1805.CrossRef
42.
Campbell M, Allen WE, Sawyer C, Vanhaesebroeck B, Trimble ER: Glucose-potentiated chemotaxis in human vascular smooth muscle is dependent on cross-talk between the PI3K and MAPK signaling pathways. Circ Res. 2004, 95: 380-388. 10.1161/01.RES.0000138019.82184.5d.CrossRef
43.
Martin MM, Buckenberger JA, Jiang J, Malana GE, Knoell DL, Feldman DS, Elton TS: TGF-beta1 stimulates human AT1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways. Am J Physiol Lung Cell Mol Physiol. 2007, 293: L790-L799. 10.1152/ajplung.00099.2007.CrossRef
44.
Westwood JA, Smyth MJ, Teng MW, Moeller M, Trapani JA, Scott AM, Smyth FE, Cartwright GA, Power BE, Hönemann D, Prince HM, Darcy PK, Kershaw MH: Adoptive transfer of T cells modified with a humanized chimeric receptor gene inhibits growth of Lewis-Y-expressing tumors in mice. Proc Natl Acad Sci USA. 2005, 102: 19051-19056. 10.1073/pnas.0504312102.CrossRef
45.
Halloran MM, Carley WW, Polverini PJ, Haskell CJ, Phan S, Anderson BJ, Woods JM, Campbell PL, Volin MV, Bäcker AE, Koch AE: Ley/H: an endothelial-selective, cytokine-inducible, angiogenic mediator. J Immunol. 2000, 164: 4868-4877.CrossRef
46.
Kudryashow V, Glunz PW, Williams LJ, Hintermann S, Danishefsky SJ, Lloyd KO: Toward optimized carbohydrate-based anticancer vaccines: epitope clustering, carrier structure, and adjuvant all influence antibody responses to Lewis y conjugates in mice. Proc Natl Acad Sci USA. 2001, 98: 3264-3269. 10.1073/pnas.051623598.CrossRef
47.
Livingston PO, Ragupathi G: Cancer vaccines targeting carbohydrate antigens. Hum Vaccin. 2006, 2: 137-143.CrossRef
Metadata
Title
Lewis y antigen promotes the proliferation of ovarian carcinoma-derived RMG-I cells through the PI3K/Akt signaling pathway
Authors
Juanjuan Liu
Bei Lin
Yingying Hao
Yue Qi
Liancheng Zhu
Feifei Li
Dawo Liu
Jianping Cong
Shulan Zhang
Masao Iwamori
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2009
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/1756-9966-28-154

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