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Regulation of carcinoembryonic antigen release from colorectal cancer cells

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Abstract

Clinical and experimental evidence suggest that circulating carcinoembryonic antigen (CEA) released from tumor cells has an instrumental role in colorectal cancer-liver metastasis. However, the precise mechanism of the regulation of the CEA release from cancer cells is not known. We investigated if the rate of CEA and another GPI-anchored protein, alkaline phosphatase (AP) release is correlated with cellular glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) expression. We also evaluated the effects of phosphatidic acid (PA), a compound known to inhibit GPI-PLD activity, on the CEA and AP release from colon cancer cells. The expression of CEA, GPI-PLD, and AP in five colon carcinoma cells (LS180, Caco2, SW742, SW1116, and HT29/219) was verified by immunoblot and real-time RT-PCR analysis. The amounts of CEA and AP released into cell culture media were determined using ELISA and a colorimetric assay, respectively. We examined the effects of PA (20–100 μM) on CEA and AP release from LS180 cells. All five cancer cell lines analyzed expressed GPI-PLD protein. While there was a positive relationship between AP release and the levels of GPI-PLD transcript expression, we found no direct correlation between CEA released from cancer cells and the GPI-PLD mRNA expression level. However, the rate of CEA release was positively associated with the level of CEA transcript expression. In comparison to controls, the release of GPI-anchored CEA and AP, but not CA19-9 was inhibited significantly by both crude and pure phosphatidic acid (by 56 and 54.5%, respectively). Using PA for inhibiting CEA release from cancer cells may have therapeutic application in preventing CRC-liver metastasis.

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References

  1. Chevinsky AH (1991) CEA in tumors of other than colorectal origin. Semin Surg Oncol 7:162–166. doi:10.1002/ssu.2980070309

    Article  PubMed  CAS  Google Scholar 

  2. Wiggers T, Arends JW, Schutte B, Volovics L, Bosman FT (1988) A multivariate analysis of pathologic prognostic indicators in large bowel cancer. Cancer 61:386–395. doi:10.1002/1097-0142(19880115)

    Article  PubMed  CAS  Google Scholar 

  3. Chan CH, Stanners CP (2007) Recent advances in the tumour biology of the GPI-anchored carcinoembryonic antigen family members CEACAM5 and CEACAM6. Curr Oncol 14:70–73. doi:10.3747/co.2007.109

    Article  PubMed  CAS  Google Scholar 

  4. Aarons CB, Bajenova O, Andrews C, Heydrick S, Bushell KN, Reed KL et al (2007) Carcinoembryonic antigen stimulated THP-1 macrophages activate endothelial cells and increase cell–cell adhesion of colorectal cancer cells. Clin Exp Metastasis 24:201–209. doi:10.1007/s10585-007-9069-7

    Article  PubMed  Google Scholar 

  5. Jessup JM, Samara R, Battle P, Laguinge LM (2004) Carcinoembryonic antigen promotes tumor cell survival in liver through an IL-10-dependent pathway. Clin Exp Metastasis 21:709–717. doi:10.1007/s10585-004-7705-z

    Article  PubMed  CAS  Google Scholar 

  6. Holt AD, Kim JT, Murrell Z, Huynh R, Stamos MJ, Kumar RR (2006) The role of carcinoembryonic antigen as a predictor of the need for preoperative computed tomography in colon cancer patients. Am Surg 72:897–901

    PubMed  Google Scholar 

  7. Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS et al (2006) ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 24:5313–5327. doi:10.1200/JCO.2006.08.2644

    Article  PubMed  CAS  Google Scholar 

  8. Jessup JM, Ishii S, Mitzoi T, Edmiston KH, Shoji Y (1999) Carcinoembryonic antigen facilitates experimental metastasis through a mechanism that does not involve adhesion to liver cells. Clin Exp Metastasis 17:481–488. doi:10.1023/A:1006685817395

    Article  PubMed  CAS  Google Scholar 

  9. Gangopadhyay A, Lazure DA, Thomas P (1998) Adhesion of colorectal carcinoma cells to the endothelium is mediated by cytokines from CEA stimulated Kupffer cells. Clin Exp Metastasis 16:703–712. doi:10.1023/A:1006576627429

    Article  PubMed  CAS  Google Scholar 

  10. Harłozińska A, Rachel F, Gawlikowski W, Richter R, Kołodziej J (1991) CEA and NCA levels in peripheral and tumour venous blood of patients with gastric and colonic carcinomas estimated by RIA and EIA methods. Eur J Surg Oncol 17:59–64

    PubMed  Google Scholar 

  11. Thomas P, Zamcheck N (1983) Role of the liver in clearance and excretion of circulating carcinoembryonic antigen (CEA). Dig Dis Sci 28:216–224. doi:10.1007/BF01295116

    Article  PubMed  CAS  Google Scholar 

  12. Goslin R, O’Brien MJ, Steele G, Mayer R, Wilson R, Corson JM et al (1981) Correlation of plasma CEA and CEA tissue staining in poorly differentiated colorectal cancer. Am J Med 71:246–253. doi:10.1016/0002-9343(81)90125-X

    Article  PubMed  CAS  Google Scholar 

  13. Wagener C, Müller-Wallraf R, Nisson S, Gröner J, Breuer H (1981) Localization and concentration of carcinoembryonic antigen (CEA) in gastrointestinal tumors: correlation with CEA levels in plasma. J Natl Cancer Inst 67:539–547

    PubMed  CAS  Google Scholar 

  14. Naghibalhossaini F, Ebadi P (2006) Evidence for CEA release from human colon cancer cells by an endogenous GPI-PLD enzyme. Cancer Lett 234:158–167. doi:10.1016/j.canlet.2005.03.028

    Article  PubMed  CAS  Google Scholar 

  15. Yamamoto Y, Hirakawa E, Mori S, Hamada Y, Kawaguchi N, Matsuura N (2005) Cleavage of carcinoembryonic antigen induces metastatic potential in colorectal carcinoma. Biochem Biophys Res Commun 333:223–229. doi:10.1016/j.bbrc.2005.05.084

    Article  PubMed  CAS  Google Scholar 

  16. Deeg MA, Verchere CB (1997) Regulation of glycosylphosphatidylinositol-specific phospholipase D secretion from βTC3 cells. Endocrinology 138:819–826. doi:10.1210/en.138.2.819

    Article  PubMed  CAS  Google Scholar 

  17. O’Brien KD, Pineda C, Chiu WS, Bowen R, Deeg MA (1999) Glycosylphosphatidylinositol-specific phospholipase D is expressed by macrophages in human atherosclerosis and colocalizes with oxidation epitopes. Circulation 99:2876–2882

    PubMed  Google Scholar 

  18. Low MG, Huang K-S (1993) Phosphatidic acid, lysophosphatidic acid, and lipid A are inhibitors of glycosylphosphatidylinositol-specific phospholipase D. Specific inhibition of a phospholipase by product analogues? J Biol Chem 268:8480–8490

    PubMed  CAS  Google Scholar 

  19. Low MG, Stütz P (1999) Inhibition of the plasma glycosylphosphatidylinositol-specific phospholipase D by synthetic analogs of lipid A and phosphatidic acid. Arch Biochem Biophys 371:332–339. doi:10.1006/abbi.1999.1436

    Article  PubMed  CAS  Google Scholar 

  20. Han JS, Nair PP (1995) Flow cytometric identification of cell surface markers on cultured human colonic cell lines using monoclonal antibodies. Cancer 76:195–200. doi:10.1002/1097-0142(19950715)76:2<195:AID-CNCR2820760206>3.0.CO;2-E

    Article  PubMed  CAS  Google Scholar 

  21. Hashino J, Fukuda Y, Oikawa S, Nakazato H, Nakanishi T (1994) Metastatic potential in nude mice of Chinese hamster ovary cells expressing human carcinoembryonic antigen. Biochem Biophys Res Commun 200:1748–1753. doi:10.1006/bbrc.1994.1655

    Article  PubMed  CAS  Google Scholar 

  22. Kim JC, Gong G, Roh SA, Park KC (1999) Carcinoembryonic antigen gene and carcinoembryonic antigen expression in the liver metastasis of colorectal carcinoma. Mol Cells 9:133–137

    PubMed  CAS  Google Scholar 

  23. Tsujioka H, Takami N, Misumi Y, Ikehara Y (1999) Intracellular cleavage of glycosylphosphatidylinositol by phospholipase D induces activation of protein kinase C alpha. Biochem J 342:449–455. doi:10.1042/0264-6021:3420449

    Article  PubMed  CAS  Google Scholar 

  24. Xiaotong H, Hannocks MJ, Hampson I, Brunner G (2002) GPI-specific phospholipase D mRNA expression in tumor cells of different malignancy. Clin Exp Metastasis 19:291–299. doi:10.1023/A:1015545407700

    Article  PubMed  CAS  Google Scholar 

  25. Metz CN, Brunner G, Choi-Muira NH, Nguyen H, Gabrilove J, Caras IW et al (1994) Release of GPI-anchored membrane proteins by a cell-associated GPI-specific phospholipase D. EMBO J 13:1741–1751

    PubMed  CAS  Google Scholar 

  26. Mann KJ, Hepworth MR, Raikwar NS, Deeg MA, Sevlever D (2004) Effect of glycosylphosphatidylinositol (GPI)-phospholipase D overexpression on GPI metabolism. Biochem J 378:641–648. doi:10.1042/BJ20031326

    Article  PubMed  CAS  Google Scholar 

  27. Giocondi MC, Seantier B, Dosset P, Milhiet PE, Le Grimellec C (2008) Characterizing the interactions between GPI-anchored alkaline phosphatases and membrane domains by AFM. Pflugers Arch 456:179–188. doi:10.1007/s00424-007-0409-x

    Article  PubMed  CAS  Google Scholar 

  28. Dietrich C, Volovyk ZN, Levi M, Thompson NL, Jacobson K (2001) Partitioning of Thy-1, GM1, and cross-linked phospholipid analogs into lipid rafts reconstituted in supported model membrane monolayers. Proc Natl Acad Sci USA 98:10642–10647. doi:10.1073/pnas.191168698

    Article  PubMed  CAS  Google Scholar 

  29. Fivaz M, Vilbois F, Thurnheer S, Pasquali C, Abrami L, Bickel PE et al (2002) Differential sorting and fate of endocytosed GPI-anchored proteins. EMBO J 21:3989–4000. doi:10.1093/emboj/cdf398

    Article  PubMed  CAS  Google Scholar 

  30. Madore N, Smith KL, Graham CH, Jen A, Brady K, Hall S et al (1999) Functionally different GPI proteins are organized in different domains on the neuronal surface. EMBO J 18:6917–6926

    Article  PubMed  CAS  Google Scholar 

  31. Legler DF, Doucey MA, Schneider P, Chapatte L, Bender FC, Bron C (2005) Differential insertion of GPI-anchored GFPs into lipid rafts of live cells. FASEB J 19:73–75. doi:10.1096/fj.03-1338fje

    PubMed  CAS  Google Scholar 

  32. Lee JY, Lee HJ, Kim MR, Myung PK, Sok DE (1999) Regulation of brain glycosylphosphatidylinositol-specific phospholipase D by natural amphiphiles. Neurochem Res 24:1577–1583. doi:10.1023/A:1021112401640

    Article  PubMed  CAS  Google Scholar 

  33. Shi ZR, Tsao D, Kim YS (1983) Subcellular distribution, synthesis, and release of carcinoembryonic antigen in cultured human colon adenocarcinoma cell lines. Cancer Res 43:4045–4049

    PubMed  CAS  Google Scholar 

  34. Lee C, Lim HK, Sakong J, Lee YS, Kim JR, Baek SH (2006) Janus kinase-signal transducer and activator of transcription mediates phosphatidic acid-induced interleukin (IL)-1beta and IL-6 production. Mol Pharmacol 69:1041–1047. doi:10.1124/mol.105.018481

    PubMed  CAS  Google Scholar 

  35. Fukami K, Takenawa T (1992) Phosphatidic acid that accumulates in platelet-derived growth factor-stimulated Balb/c 3T3 cells is a potential mitogenic signal. J Biol Chem 267:10988–10993

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work contains parts of the doctoral thesis of Abbas Pakdel. The authors would like to thank Dr. Mahmood Vessal for careful reading of the manuscript. This study was supported by a grant from the Vice Chancellor for Research, Shiraz University of Medical Sciences.

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Authors and Affiliations

  1. Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Zand Street, Shiraz, Fars, Iran

    Abbas Pakdel, Fakhraddin Naghibalhossaini & Pooneh Mokarram

  2. Autoimmune Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Fakhraddin Naghibalhossaini

  3. Cancer Gene Therapy Laboratory, Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran

    Mansooreh Jaberipour & Ahmad Hosseini

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  1. Abbas Pakdel
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Correspondence to Fakhraddin Naghibalhossaini.

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Pakdel, A., Naghibalhossaini, F., Mokarram, P. et al. Regulation of carcinoembryonic antigen release from colorectal cancer cells. Mol Biol Rep 39, 3695–3704 (2012). https://doi.org/10.1007/s11033-011-1144-0

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