SEARCH:   Advanced

Blood, 1 November 2004, Vol. 104, No. 9, pp. 2886-2892. Prepublished online as a Blood First Edition Paper on June 24, 2004; DOI 10.1182/blood-2004-05-1760. This Article Full Text (PDF) All Versions of this Article: 2004-05-1760v1 104/9/2886    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 Le Gouill, S. Articles by Anderson, K. C Search for Related Content PubMed PubMed Citation Articles by Le Gouill, S. Articles by Anderson, K. C Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 7, 2004 Accepted June 11, 2004 VEGF induces MCL-1 upregulation and protects multiple myeloma cells against apoptosis Steven Le Gouill, Klaus Podar, Martine Amiot, Teru Hideshima, Dharminder Chauhan, Kenji Itshitsuka, Shaji Kumar, Noopur Raje, Paul G Richardson, Jean-Luc Harousseau, and Kenneth C Anderson* Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; U601, INSERM U0601, Institut de Biologie, Nantes, France, Metropolitan; Service d'Hematologie Clinique, Hotel-Dieu CHU de Nantes, Nantes, Cedex 01, France, Metropolitan Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA U601, INSERM U0601, Institut de Biologie, Nantes, France, Metropolitan * Corresponding author; email: Kenneth_anderson{at}dfci.harvard.edu. Interleukin-6 (IL-6) triggers multiple myeloma (MM) cell proliferation and protects against apoptosis by upregulating Myeloid-cell-leukemia 1 (Mcl-1). Vascular endothelial growth factor (VEGF) induces modest proliferation of MM cells and induces IL-6 secretion in a paracrine loop involving MM cells and bone marrow stromal cells. Using murine embryonic fibroblast cell line as a model (Mcl-1wt/wt and Mcl-1/null MEFs), we here demonstrate that deletion of Mcl-1 reduces fetal bovine serum (FBS), VEGF, and IL-6 induced-proliferation. We also show that VEGF upregulates Mcl-1 expression in a time and dose manner in 3 human MM cell lines and MM patient cells. Importantly, we demonstrate that the pan-VEGF inhibitor, GW654652, inhibits VEGF induced-upregulation of Mcl-1, and as with Mcl-1 siRNA is associated with decreased proliferation and induction of apoptosis. Finally, we show that VEGF protects MM patient cells against FBS starvation-induced apoptosis. Our studies therefore demonstrate that VEGF-induced MM cell proliferation and survival is mediated via Mcl-1, providing the preclinical framework for novel therapeutics targeting both Mcl-1 and/or VEGF to improve patient outcome in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. V. Kurtova, K. Balakrishnan, R. Chen, W. Ding, S. Schnabl, M. P. Quiroga, M. Sivina, W. G. Wierda, Z. Estrov, M. J. Keating, et al. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance Blood, November 12, 2009; 114(20): 4441 - 4450. [Abstract] [Full Text] [PDF] V. Bhandari, R. Choo-Wing, C. G. Lee, K. Yusuf, J. H. Nedrelow, N. Ambalavanan, H. Malkus, R. J. Homer, and J. A. Elias Developmental Regulation of NO-Mediated VEGF-Induced Effects in the Lung Am. J. Respir. Cell Mol. Biol., October 1, 2008; 39(4): 420 - 430. [Abstract] [Full Text] [PDF] P. M. Elias, J. Arbiser, B. E. Brown, H. Rossiter, M.-Q. Man, F. Cerimele, D. Crumrine, R. Gunathilake, E. H. Choi, Y. Uchida, et al. Epidermal Vascular Endothelial Growth Factor Production Is Required for Permeability Barrier Homeostasis, Dermal Angiogenesis, and the Development of Epidermal Hyperplasia: Implications for the Pathogenesis of Psoriasis Am. J. Pathol., September 1, 2008; 173(3): 689 - 699. [Abstract] [Full Text] [PDF] M. Koldehoff, D. W. Beelen, and A. H. Elmaagacli Small-molecule inhibition of proteasome and silencing by vascular endothelial cell growth factor-specific siRNA induce additive antitumor activity in multiple myeloma J. Leukoc. Biol., August 1, 2008; 84(2): 561 - 576. [Abstract] [Full Text] [PDF] D. Allard, N. Figg, M. R. Bennett, and T. D. Littlewood Akt Regulates the Survival of Vascular Smooth Muscle Cells via Inhibition of FoxO3a and GSK3 J. Biol. Chem., July 11, 2008; 283(28): 19739 - 19747. [Abstract] [Full Text] [PDF] A. De Biasio, J. A. Vrana, P. Zhou, L. Qian, C. K. Bieszczad, K. E. Braley, A. M. Domina, S. J. Weintraub, J. M. Neveu, W. S. Lane, et al. N-terminal Truncation of Antiapoptotic MCL1, but Not G2/M-induced Phosphorylation, Is Associated with Stabilization and Abundant Expression in Tumor Cells J. Biol. Chem., August 17, 2007; 282(33): 23919 - 23936. [Abstract] [Full Text] [PDF] S.-R. A. Hussain, C. M. Cheney, A. J. Johnson, T. S. Lin, M. R. Grever, M. A. Caligiuri, D. M. Lucas, and J. C. Byrd Mcl-1 Is a Relevant Therapeutic Target in Acute and Chronic Lymphoid Malignancies: Down-Regulation Enhances Rituximab-Mediated Apoptosis and Complement-Dependent Cytotoxicity Clin. Cancer Res., April 1, 2007; 13(7): 2144 - 2150. [Abstract] [Full Text] [PDF] A. Muto, M. Hori, Y. Sasaki, A. Saitoh, I. Yasuda, T. Maekawa, T. Uchida, K. Asakura, T. Nakazato, T. Kaneda, et al. Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor Mol. Cancer Ther., March 1, 2007; 6(3): 987 - 994. [Abstract] [Full Text] [PDF] P. G. Richardson, T. Hideshima, and K. C. Anderson Plasma cell dyscrasias ASH Self-Assessment Program, January 1, 2007; 2007(1): 298 - 327. [Full Text] [PDF] G. Bisping, M. Kropff, D. Wenning, B. Dreyer, S. Bessonov, F. Hilberg, G. J. Roth, G. Munzert, M. Stefanic, M. Stelljes, et al. Targeting receptor kinases by a novel indolinone derivative in multiple myeloma: abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups Blood, March 1, 2006; 107(5): 2079 - 2089. [Abstract] [Full Text] [PDF] E. S. Henson, X. Hu, and S. B. Gibson Herceptin Sensitizes ErbB2-Overexpressing Cells to Apoptosis by Reducing Antiapoptotic Mcl-1 Expression Clin. Cancer Res., February 1, 2006; 12(3): 845 - 853. [Abstract] [Full Text] [PDF] J. E. Karp, A. Passaniti, I. Gojo, S. Kaufmann, K. Bible, T. S. Garimella, J. Greer, J. Briel, B. D. Smith, S. D. Gore, et al. Phase I and Pharmacokinetic Study of Flavopiridol followed by 1-{beta}-D-Arabinofuranosylcytosine and Mitoxantrone in Relapsed and Refractory Adult Acute Leukemias Clin. Cancer Res., December 1, 2005; 11(23): 8403 - 8412. [Abstract] [Full Text] [PDF] M. Rahmani, E. M. Davis, C. Bauer, P. Dent, and S. Grant Apoptosis Induced by the Kinase Inhibitor BAY 43-9006 in Human Leukemia Cells Involves Down-regulation of Mcl-1 through Inhibition of Translation J. Biol. Chem., October 21, 2005; 280(42): 35217 - 35227. [Abstract] [Full Text] [PDF] T. Hideshima, D. Chauhan, P. Richardson, and K. C. Anderson Identification and Validation of Novel Therapeutic Targets for Multiple Myeloma J. Clin. Oncol., September 10, 2005; 23(26): 6345 - 6350. [Abstract] [Full Text] [PDF] N. Raje, S. Kumar, T. Hideshima, A. Roccaro, K. Ishitsuka, H. Yasui, N. Shiraishi, D. Chauhan, N. C. Munshi, S. R. Green, et al. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma Blood, August 1, 2005; 106(3): 1042 - 1047. [Abstract] [Full Text] [PDF] H. Yasui, T. Hideshima, M. Hamasaki, A. M. Roccaro, N. Shiraishi, S. Kumar, P. Tassone, K. Ishitsuka, N. Raje, Y.-T. Tai, et al. SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma Blood, July 15, 2005; 106(2): 706 - 712. [Abstract] [Full Text] [PDF] T. Hideshima, J. E. Bradner, J. Wong, D. Chauhan, P. Richardson, S. L. Schreiber, and K. C. Anderson Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma PNAS, June 14, 2005; 102(24): 8567 - 8572. [Abstract] [Full Text] [PDF] A. Nencioni, L. Wille, G. Dal Bello, D. Boy, G. Cirmena, S. Wesselborg, C. Belka, P. Brossart, F. Patrone, and A. Ballestrero Cooperative Cytotoxicity of Proteasome Inhibitors and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand in Chemoresistant Bcl-2-Overexpressing Cells Clin. Cancer Res., June 1, 2005; 11(11): 4259 - 4265. [Abstract] [Full Text] [PDF] M. Hamasaki, T. Hideshima, P. Tassone, P. Neri, K. Ishitsuka, H. Yasui, N. Shiraishi, N. Raje, S. Kumar, D. H. Picker, et al. Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo Blood, June 1, 2005; 105(11): 4470 - 4476. [Abstract] [Full Text] [PDF] A. Nencioni, F. Hua, C. P. Dillon, R. Yokoo, C. Scheiermann, M. H. Cardone, E. Barbieri, I. Rocco, A. Garuti, S. Wesselborg, et al. Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis Blood, April 15, 2005; 105(8): 3255 - 3262. [Abstract] [Full Text] [PDF] K. Podar and K. C. Anderson The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications Blood, February 15, 2005; 105(4): 1383 - 1395. [Abstract] [Full Text] [PDF]

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020