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Molecular mechanisms of CD99-induced caspase-independent cell death and cell–cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators

Oncogene volume 23, pages 5664–5674 (2004)Cite this article

Abstract

CD99 is a unique 32-kDa cell surface molecule with broad cellular expression but still poorly understood biological functions. In cancer cells, CD99 is highly expressed in virtually all Ewing's sarcoma (ES). Engagement of CD99 induces fast homotypic aggregation of ES cells and caspase-independent apoptosis. In this study, we analysed signal transduction after CD99 engagement on ES cells. Findings obtained with selective inhibitors indicated that only actin cytoskeleton integrity was essential for cell–cell adhesion and apoptosis of ES cells. Indeed, CD99 stimulation induced actin repolymerization, further supporting the role of cytoskeleton in CD99 signaling. Gene expression profiling of ES cells after CD99 engagement showed modulation in the expression of 32 genes. Among the pool of upregulated genes reported to be involved in cell adhesion, we chose to analyse the role of zyxin, a cytoplasmic adherens junction protein found to play a role in the regulation of the actin cytoskeleton. Overexpression of zyxin after CD99 ligation was confirmed by real-time PCR and Western blot. Treatment of ES cells with zyxin antisense oligonucleotides inhibited CD99-induced cell aggregation and apoptosis, suggesting a functional role for this protein. Therefore, our findings indicate that CD99 functions occur through reorganization of cytoskeleton and identify actin and zyxin as the early signaling events driven by CD99 engagement.

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References

  • Alberti I, Bernard G, Rouquette-Jazdanian AK, Pelassy C, Pourtein M, Aussel C and Bernard A . (2002). FASEB J., 16, 1946–1948.

  • Ambros IM, Ambros PF, Strehl S, Kovar H, Gadner H and Salzer Kuntschik M . (1991). Cancer, 67, 1886–1893.

  • Aussel C, Bernard G, Breittmayer JP, Pelassy C, Zoccola D and Bernard A . (1993). Biochemistry, 32, 10096–10101.

  • Banting GS, Pym B, Darling SM and Goodfellow PN . (1989). Mol. Immunol., 26, 181–188.

  • Beckerle MC . (1997). Bioessays, 19, 949–957.

  • Bernard A, Aubrit F, Raynal B, Pham D and Boumsell LA . (1988). J. Immunol., 14, 1802–1807.

  • Bernard G, Breittmayer JP, de Matteis M, Trampont P, Hofman P, Senik A and Bernard A . (1997). J. Immunol., 158, 2543–2550.

  • Bernard G, Raimondi V, Alberti I, Pourtein M, Widjenes J, Ticchioni M and Bernard A . (2000). Eur. J. Immunol., 30, 3061–3065.

  • Bernard G, Zoccola D, Deckert M, Breittmayer JP, Aussel C and Bernard A . (1995). J. Immunol., 154, 26–32.

  • Choi EY, Park WS, Jung KC, Kim SH, Kim YY, Lee WJ and Park SH . (1998). J. Immunol., 161, 749–754.

  • Crawford AW and Beckerle MC . (1991). J. Biol. Chem., 266, 5847–5853.

  • Dworzak MN, Fritsch G, Fleischer C, Printz D, Fröschl G, Buchinger P, Mann G and Gadner H . (1999). Br. J. Haematol., 105, 690–695.

  • Fidler I.J . (1997). Cancer: Principles and Practise of Oncology, 5th edn Lippincott-Raven Publishers: Philadephia, US.

    Google Scholar 

  • Fisher C . (1998). Ann. Diagn. Pathol., 2, 401–421.

  • Gelin C, Aubrit F, Phalipon A, Raynal B, Cole S, Kaczorek M and Bernard A . (1989). EMBO J., 8, 3253–3259.

  • Gelin C, Zilber MT, Jovanovich D and Boumsell L . (1995). Leucocyte, Typing V. White Cell Differentiation Antigens. Proceedings of the Fifth International Workshop and Conference. Oxford University Press: Oxford, England.

    Google Scholar 

  • Goodfellow PJ, Darling SM, Thomas NS and Goodfellow PN . (1986). Science, 234, 740–743.

  • Granter SR, Renshaw AA, Fletcher CD, Bhan AK and Rosenberg AE . (1996). Hum. Pathol., 27, 1273–1276.

  • Hahn JH, Kim MK, Choi EY, Kim SH, Sohn HW, Ham DI, Chung DH, Kim TJ, Lee WJ, Park CK, Ree HJ and Park SH . (1997). J. Immunol., 159, 2250–2258.

  • Hahn MJ, Yoon SS, Sohn HW, Song HG, Park SH and Kim TJ . (2000). FEBS Lett., 470, 350–354.

  • Jung KC, Park WS, Bae YM, Hahn JH, Hahn K, Lee H, Lee HW, Koo HJ, Shin HJ, Shin HS, Park YE and Park SH . (2002). J. Korean Med. Sci., 17, 483–489.

  • Kasinrerk W, Tokrasinwit N, Moonsom S and Stockinger H . (2000). Immunol. Lett., 71, 33–41.

  • Kettunen E, Nissen AM, Ollikainen T, Taavitsainen M, Tapper J, Mattson K, Linnainmaa K, Knuutila S and El-Rifai W . (2001). Int. J. Cancer, 9, 492–496.

  • Kim MK, Choi YL, Kim MK, Kim SH, Choi EY, Park WS, Bae YM, Woo SH and Park SH . (2003). FEBS Lett., 546, 379–384.

  • Kim SH, Choi EY, Shin YK, Kim TJ, Chung DH, Chang SI, Kim NK and Park SH . (1998). Blood, 92, 4287–44295.

  • Kim SH, Shin YK, Lee I, Bae YM, Sohn HW, Suh YH, Ree HJ, Rowe M and Park SH . (2000). Blood, 95, 294–300.

  • Kovar H, Dworzak M, Strehl S, Schnell E, Ambros IM, Ambros PF and Gadner H . (1990). Oncogene, 45, 1067–1070.

  • Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, vanSchie RC, LaFace DM and Green DR . (1995). J. Exp. Med., 182, 1545–1556.

  • Mateo V, Brown EJ, Biron G, Rubio M, Fisher A, Le Deist F and Sarfati M . (2002). Blood, 100, 2882–2890.

  • Nix DA and Beckerle MC . (1997). J. Biol. Chem., 138, 1139–1147.

  • Nix DA, Fradelizi J, Bockholt S, Menichi B, Louvard D, Friederich E and Beckerle MC . (2001). J. Biol. Chem., 276, 34759–34767.

  • Pettersen RD, Bernard G, Olafsen MK, Pourtein M and Lie SO . (2001). J. Immunol., 16, 4931–4942.

  • Pettersen RD, Hestdal K, Olafsen MK, Lie SO and Lindberg FP . (1999). J. Immunol., 16, 7031–7040.

  • Preda P, Pileri S and Pasquinelli G . (1995). Microsc. Technol., 32, 75–76.

  • Ramani P, Rampling D and Link M . (1993). Histopathology, 23, 557–561.

  • Schenkel AR, Mamdouh Z, Chen X, Liebman RM and Muller WA . (2002). Nat. Immunol., 3, 143–150.

  • Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S and Peter ME . (1998). Eur. J. Biochem., 254, 439–459.

  • Scotlandi K, Baldini N, Cerisano V, Manara MC, Benini S, Serra M, Lollini PL, Nanni P, Nicoletti G, Bernard G, Bernard A and Picci P . (2000). Cancer Res., 60, 5134–5142.

  • Scotlandi K, Serra M, Manara MC, Benini S, Sarti M, Maurici D, Lollini PL, Picci P, Bertoni F and Baldini N . (1996). Hum. Pathol., 27, 408–416.

  • Scotlandi K, Serra M, Nicoletti G, Vaccari M, Manara MC, Nini G, Landuzzi L, Colacci A, Bacci G, Bertoni F, Picci P, Campanacci M and Baldini N . (1996). Cancer Res., 56, 2434–2439.

  • Shen J, Zhau HE, Hursting SD and Chung LW . (1998). Mol. Carcinogen., 23, 13–19.

  • Sohn HW, Choi EY, Kim SH, Lee I, Chung DH, Sung UA, Hwang DH, Cho SS, Jun BH, Jang JJ, Chi JG and Park SH . (1998). Am. J. Pathol., 153, 1937–1945.

  • Sohn HW, Shin YK, Bae YM, Suh YH, Kim MK, Kim TJ, Jung KC, Park WS, Park CS, Chung DH, Ahn K, Kim IS, Ko YH, Bang YJ, Kim CW and Park SH . (2001). J. Immunol., 166, 787–794.

  • Waclavicek M, Majdic O, Stulnig T, Berger M, Sunder-Plassmann R, Zlabinger GJ, Baumruker T, Stöckl J, Ebner C, Knapp W and Pickl WF . (1998). J. Immunol., 61, 4671–4678.

  • Wingett D, Forcier K and Nielson CP . (1999). Cell. Immunol., 193, 17–23.

  • Yoon SS, Jung KI, Choi Y, Choi EY, Lee I, Park SH and Kim TJ . (2003). FEBS Lett., 540, 217–222.

  • Zen K., Masuda J and Ogata J . (1996). Immunobiology, 195, 323–333.

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Acknowledgements

This work was supported by grants of the Italian Association for Cancer Research, Italian Ministry of Health and, in Finland, by the Cancer Society and Helsinki University Central Hospital in Finland. We thank the Italian Foundation for Cancer Research for providing a fellowship to VC and SP.

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Authors and Affiliations

  1. Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, Bologna, 40136, Italy

    Vanessa Cerisano, Stefania Perdichizzi, Maria Cristina Manara, Stefania Benini, Piero Picci & Katia Scotlandi

  2. Departments of Pathology and Medical Genetics, Haartman Institute and University of Helsinki, Helsinki, FIN-00014, Finland

    Yan Aalto, Bálint Nagy & Sakari Knuutila

  3. Unité INSERM UMR 576, Hôspital de l'Archet, Nice, Cedex 3, France

    Ghislaine Bernard & Alain Bernard

  4. Dipartimento Clinico di Scienze Radiologiche e Istocitopatologiche, Università di Bologna, Bologna, Italy

    Giovanna Cenacchi & Paola Preda

  5. ITOI-CNR, Unit of Bologna, c/o Istituti Ortopedici Rizzoli, Bologna, 40136, Italy

    Giovanna Lattanzi

  6. Immunotherapy and Gene Therapy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, 20133, Italy

    Mario Paolo Colombo

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  1. Vanessa Cerisano
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Correspondence to Katia Scotlandi.

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Cerisano, V., Aalto, Y., Perdichizzi, S. et al. Molecular mechanisms of CD99-induced caspase-independent cell death and cell–cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators. Oncogene 23, 5664–5674 (2004). https://doi.org/10.1038/sj.onc.1207741

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