Bevacizumab attenuates major signaling cascades and elF4E translation initiation factor in multiple myeloma cells
Bevacizumab attenuates major signaling cascades and elF4E translation initiation factor in multiple myeloma cells
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DOI：
10.1038/labinvest.2011.162
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发表时间：
2012-02-01
影响因子：
5
通讯作者：
Lishner, Michael
中科院分区：
文献类型：
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作者：
Attar-Schneider, Oshrat;Drucker, Liat;Lishner, Michael
多发性骨髓瘤（MM），浆细胞的恶性肿瘤，仍然是致命的，尽管引入了新的治疗，部分原因是体液因素，包括血管内皮生长因子（VEGF），在他们的微环境。本研究的目的是探索贝伐单抗直接抗VEGF治疗MM细胞的疗效。特别注意VEGF抑制对蛋白质翻译起始的影响。在塑料上培养的MM细胞（系，骨髓（BM）样品）上进行实验。以临床使用的抗VEGF抗体贝伐单抗作为平台实现VEGF的抑制，并评估其对活力、增殖和存活的影响。还测定了对MM细胞生物学确定重要性的VEGF下游信号，特别强调翻译起始因子eIF 4 E。我们发现阻断VEGF对MM细胞有害并导致细胞停滞。这在MM细胞系以及原代BM样品（BM MM）中得到证实。确定了贝伐珠单抗诱导的关键信号传导效应物的常见衰减：VEGFR 1、mTOR、c-Myc、Akt、STAT 3（细胞系）和eIF 4 E翻译起始因子（细胞系和BM）。ERK 1/2对贝伐珠单抗表现出多样化的反应（线）。利用组成型表达Akt的MM模型，我们表明贝伐单抗对活力和eIF 4 E状态的影响是Akt依赖性的。值得注意的是，贝伐珠单抗的作用是在高浓度（2 mg/ml）下实现的，但显示具有特异性。这些结果表明，贝伐珠单抗对MM中关键激活的主要途径具有直接影响，这与其对血管生成的既定作用无关。VEGF抑制对MM细胞的细胞生长抑制作用强调了其在联合治疗中的潜力，我们的研究结果表明，关于其对翻译起始的影响，不平衡细胞蛋白质稳态的药物可能特别有效。实验室调查（2012）92，178-190; doi：10.1038/labinvest.2011.162; 2011年11月14日在线发表
Multiple myeloma (MM), a malignancy of plasma cells, remains fatal despite introduction of novel therapies, partially due to humoral factors, including vascular endothelial growth factor (VEGF), in their microenvironment. The aim of this study was to explore the efficacy of anti-VEGF treatment with bevacizumab directly on MM cells. Particular attention was directed to the affect of VEGF inhibition on protein translation initiation. Experiments were conducted on MM cells (lines, bone marrow (BM) samples) cultured on plastic. Inhibition of VEGF was achieved with the clinically employed anti-VEGF antibody, bevacizumab, as a platform and its consequences on viability, proliferation, and survival was assessed. VEGF downstream signals of established importance to MM cell biology were assayed as well, with particular emphasis on translation initiation factor elF4E. We showed that blocking VEGF is deleterious to the MM cells and causes cytostasis. This was evidenced in MM cell lines, as well as in primary BM samples (BM MM). A common bevacizumab-induced attenuation of critical signaling effectors was determined: VEGFR1, mTOR, c-Myc, Akt, STAT3, (cell lines) and elF4E translation initiation factor (lines and BM). ERK1/2 displayed a variegated response to bevacizumab (lines). Utilizing a constitutively Akt-expressing MM model, we showed that the effect of bevacizumab on viability and elF4E status is Akt-dependent. Of note, the effect of bevacizumab was achieved with high concentrations (2 mg/ml), but was shown to be specific. These findings demonstrate that bevacizumab has a direct influence on major pathways critically activated in MM that is independent from its established effect on angiogenesis. The cytostatic effect of VEGF inhibition on MM cells underscores its potential in combined therapy, and our findings, regarding its influence on translation initiation, suggest that drugs that unbalance cellular proteostasis may be particularly effective. Laboratory Investigation (2012) 92, 178-190; doi: 10.1038/labinvest.2011.162; published online 14 November 2011