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: Contribution to journalArticle

133 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2886-2892
Number of pages7
JournalBlood
Volume104
Issue number9
DOIs
StatePublished - Nov 1 2004

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis'. Together they form a unique fingerprint.

  • Cite this

    Le Gouill, S., Podar, K., Amiot, M., Hideshima, T., Chauhan, D., Ishitsuka, K., Kumar, S., Raje, N., Richardson, P. G., Harousseau, J. L., & Anderson, K. C. (2004). VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis. Blood, 104(9), 2886-2892. https://doi.org/10.1182/blood-2004-05-1760