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

Steven Le Gouill, Klaus Podar, Martine Amiot, Teru Hideshima, Dharminder Chauhan, Kenji Ishitsuka, Shaji Kumar, Noopur Raje, Paul G Richardson, Jean-Luc Harousseau, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

155 Citations (Scopus)

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-1 wt/wt and Mcl-1 Δ/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.

Original languageEnglish
Pages (from-to)2886-2892
Number of pages7
JournalBlood
Volume104
Issue number9
DOIs
Publication statusPublished - 01 Nov 2004
Externally publishedYes

Keywords

  • Animals
  • Apoptosis/drug effects
  • Bone Marrow/pathology
  • Cell Line
  • Cell Proliferation
  • Culture Media, Serum-Free/pharmacology
  • Humans
  • Interleukin-6/pharmacology
  • Mice
  • Multiple Myeloma/pathology
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins/biosynthesis
  • Proto-Oncogene Proteins c-bcl-2/biosynthesis
  • RNA, Small Interfering/pharmacology
  • Serum Albumin, Bovine/pharmacology
  • Tumor Cells, Cultured
  • Up-Regulation/drug effects
  • Vascular Endothelial Growth Factor A/pharmacology

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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