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Blood, 15 July 2005, Vol. 106, No. 2, pp. 658-667. Prepublished online as a Blood First Edition Paper on March 22, 2005; DOI 10.1182/blood-2004-09-3585. This Article Full Text (PDF) All Versions of this Article: 2004-09-3585v1 106/2/658    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Saumet, A. Articles by Dubernard, V. Search for Related Content PubMed PubMed Citation Articles by Saumet, A. Articles by Dubernard, V. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 15, 2004 Accepted March 11, 2005 Type 3-repeat/C-terminal domain of thrombospondin-1 triggers caspase-independent cell death through CD47/v3 in promyelocytic leukemia NB4 cells Anne Saumet, Mouna Ben Slimane, Michel Lanotte, Jack Lawler, and Veronique Dubernard* Institut National de la Sante et de la Recherche Medicale, INSERM U-685, Paris, France Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA Institut National de la Sante et de la Recherche Medicale, INSERM U-685, Paris, France; Centre de Recherche sur les Maladies du Sang et Virologie Experimentale de l'Association Claude Bernard, Hopital Saint-Louis, Paris, France * Corresponding author; email: dubernard{at}stlouis.inserm.fr. By means of its anti-angiogenic activity, thrombospondin-1 (TSP-1) exerts indirect antitumoral action on solid tumors. Here, we investigated potential antitumor action in an in vitro cell model for promyelocytic leukemia (NB4-LR1), resistant to retinoid maturation. Purified soluble TSP-1 added to cultures induced a strong dose-dependent growth inhibition and a slowly developing maturation-independent cell death. Recombinant fragments of TSP-1 allowed to map these activities to its type 3-repeat/C-terminal domain, features that are distinct from those of TSP-1 action on solid tumors, previously ascribed to the type 1-repeat domain. Cell death in leukemia was characterized as a caspase-independent mechanism, without DNA fragmentation, but phosphatidylserine externalization followed by membrane permeabilization. Mitochondria membrane depolarization was inherent to TSP-1 action but did not produce release of death-promoting proteins (e.g. non-caspase apoptosis regulators, AIF, endonuclease G or Omi/HtrA2 or the caspase regulators, cytochrome c or Smac/Diablo). Although detected, ROS production was likely not involved in the death process. Finally, receptor agonist RFYVVM and RGD peptides indicated that TSP-1 death effects are mediated by membrane receptors CD47 and v3. These results demonstrated a new domain specific anti-tumoral activity of TSP-1 on a leukemia cell line, which extends TSP-1 therapeutical potential outside the area of vascularized solid tumors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. A. Pallero, C. A. Elzie, J. Chen, D. F. Mosher, and J. E. Murphy-Ullrich Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis FASEB J, November 1, 2008; 22(11): 3968 - 3979. [Abstract] [Full Text] [PDF] M. Bras, V. J. Yuste, G. Roue, S. Barbier, P. Sancho, C. Virely, M. Rubio, S. Baudet, J. E. Esquerda, H. Merle-Beral, et al. Drp1 Mediates Caspase-Independent Type III Cell Death in Normal and Leukemic Cells Mol. Cell. Biol., October 15, 2007; 27(20): 7073 - 7088. [Abstract] [Full Text] [PDF] A. Krispin, Y. Bledi, M. Atallah, U. Trahtemberg, I. Verbovetski, E. Nahari, O. Zelig, M. Linial, and D. Mevorach Apoptotic cell thrombospondin-1 and heparin-binding domain lead to dendritic-cell phagocytic and tolerizing states Blood, November 15, 2006; 108(10): 3580 - 3589. [Abstract] [Full Text] [PDF] J. R. Inglefield, C. J. Larson, S. J. Gibson, H. Lebrec, and R. L. Miller Apoptotic Responses in Squamous Carcinoma and Epithelial Cells to Small-Molecule Toll-like Receptor Agonists Evaluated with Automated Cytometry J Biomol Screen, September 1, 2006; 11(6): 575 - 585. [Abstract] [PDF] R. van Amerongen and A. Berns TXR1-mediated thrombospondin repression: a novel mechanism of resistance to taxanes? Genes & Dev., August 1, 2006; 20(15): 1975 - 1981. [Full Text] [PDF]

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