Blood Journal
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VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis

  1. Steven Le Gouill,
  2. Klaus Podar,
  3. Martine Amiot,
  4. Teru Hideshima,
  5. Dharminder Chauhan,
  6. Kenji Ishitsuka,
  7. Shaji Kumar,
  8. Noopur Raje,
  9. Paul G. Richardson,
  10. Jean-Luc Harousseau, and
  11. Kenneth C. Anderson
  1. From the Jerome Lipper Multiple Myeloma Center Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and the Institut National de la Santé et de la Recherche Médicale (INSERM) U0601, Institut de biologie and Service d'hématologie clinique, Hôtel-Dieu Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France.

Abstract

Interleukin-6 (IL-6) triggers multiple myeloma (MM) cell proliferation and protects against apoptosis by up-regulating 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 lines as a model (Mcl-1wt/wt and Mcl-1Δ/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 up-regulates Mcl-1 expression in a time- and dose-dependent manner in 3 human MM cell lines and MM patient cells. Importantly, we demonstrate that the pan-VEGF inhibitor, GW654652, inhibits VEGF-induced up-regulation 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 are mediated via Mcl-1, providing the preclinical framework for novel therapeutics targeting Mcl-1 and/or VEGF to improve patient outcome in MM.

  • Submitted May 7, 2004.
  • Accepted June 11, 2004.
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