| First Author | Le Gouill S | Year | 2004 |
| Journal | Blood | Volume | 104 |
| Issue | 9 | Pages | 2886-92 |
| PubMed ID | 15217829 | Mgi Jnum | J:94280 |
| Mgi Id | MGI:3511737 | Doi | 10.1182/blood-2004-05-1760 |
| Citation | Le Gouill S, et al. (2004) VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis. Blood 104(9):2886-92 |
| abstractText | 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. |
