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

Blood
S Le GouillKenneth C Anderson

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(Delta/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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Citations

Jan 6, 2007·Annals of Hematology·Francesco A PiazzaGianpietro Semenzato
Oct 15, 2010·International Journal of Hematology·Hao ChenLing Pan
Mar 19, 2011·Cell Death and Differentiation·P N Kelly, A Strasser
Aug 19, 2011·Molecular & Cellular Proteomics : MCP·Yun XiangJohn M Koomen
Dec 29, 2005·Lymphatic Research and Biology·Carolyn YongMelody A Swartz
Dec 13, 2006·TheScientificWorldJournal·Janice Jin HwangKenneth C Anderson
Apr 29, 2008·American Journal of Respiratory Cell and Molecular Biology·Vineet BhandariJack A Elias
Nov 16, 2004·International Journal of Hematology·Marcela OanceaAlexandru Almasan
Jun 7, 2005·Proceedings of the National Academy of Sciences of the United States of America·Teru HideshimaKenneth C Anderson
Jun 29, 2014·Blood Cells, Molecules & Diseases·Flavia StellaIrma Slavutsky
Apr 9, 2014·The Journal of Experimental Medicine·Yinan Wang, Deepta Bhattacharya
May 22, 2010·Journal of Cancer Research and Clinical Oncology·Yu-Quan XiongZhao-You Tang
Apr 13, 2007·Expert Review of Anticancer Therapy·Klaus PodarKenneth C Anderson
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Jun 15, 2010·FEBS Letters·Luke W ThomasSteven W Edwards
Nov 13, 2014·Journal of Cellular Biochemistry·Jiyun LeeKi-Chul Hwang
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