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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.
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NEOPLASIA
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, and
Kenneth C. Anderson
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.
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-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 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.
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