Le Gouill Steven, Podar Klaus, Amiot Martine, Hideshima Teru, Chauhan Dharminder, Ishitsuka Kenji, Kumar Shaji, Raje Noopur, Richardson Paul G, Harousseau Jean-Luc, Anderson Kenneth C
Jerome Lipper Multiple Myeloma Center Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Blood. 2004 Nov 1;104(9):2886-92. doi: 10.1182/blood-2004-05-1760. Epub 2004 Jun 24.
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.
白细胞介素-6（IL-6）通过上调髓样细胞白血病1（Mcl-1）触发多发性骨髓瘤（MM）细胞增殖并保护其免受凋亡。血管内皮生长因子（VEGF）诱导MM细胞适度增殖，并在涉及MM细胞和骨髓基质细胞的旁分泌环中诱导IL-6分泌。我们以小鼠胚胎成纤维细胞系为模型（Mcl-1（野生型/野生型）和Mcl-1（缺失/缺失）MEF），在此证明Mcl-1的缺失会降低胎牛血清（FBS）、VEGF和IL-6诱导的增殖。我们还表明，VEGF在3种人类MM细胞系和MM患者细胞中以时间和剂量依赖性方式上调Mcl-1表达。重要的是，我们证明泛VEGF抑制剂GW654652抑制VEGF诱导的Mcl-1上调，并且与Mcl-1 siRNA一样，与增殖减少和凋亡诱导有关。最后，我们表明VEGF保护MM患者细胞免受FBS饥饿诱导的凋亡。因此，我们的研究表明，VEGF诱导的MM细胞增殖和存活是通过Mcl-1介导的，为靶向Mcl-1和/或VEGF的新型疗法改善MM患者的预后提供了临床前框架。
