Metabolic alterations underlying Bevacizumab therapy in glioblastoma cells.
Metabolic alterations underlying Bevacizumab therapy in glioblastoma cells.
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DOI：
10.18632/oncotarget.21761
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发表时间：
2017-11-28
期刊：
影响因子：
--
通讯作者：
Martinho O
中科院分区：
文献类型：
--
作者：
Miranda-Gonçalves V;Cardoso-Carneiro D;Valbom I;Cury FP;Silva VA;Granja S;Reis RM;Baltazar F;Martinho O
使用贝伐单抗的抗VEGF疗法被批准用于胶质母细胞瘤治疗，然而，已知肿瘤获得抗性并且在治疗后最终变得甚至更具侵袭性和浸润性。在本研究中，我们旨在阐明胶质母细胞瘤体外模型中贝伐单抗耐药的潜在细胞机制。使用一组胶质母细胞瘤细胞系，我们发现贝伐单抗能够阻断肿瘤细胞分泌的VEGF并内化至细胞质，从而在体外诱导细胞毒性。我们进一步发现，贝伐珠单抗增加了缺氧（HIF-1α和CAIX）和糖酵解标志物（GLUT 1和MCT 1）的表达，导致葡萄糖摄取和乳酸产生增加。此外，我们发现肿瘤细胞消耗的部分葡萄糖可以储存为糖原，阻碍贝伐单抗治疗后的细胞死亡。重要的是，我们发现糖酵解代谢的这种变化独立于缺氧发生，并且发生在线粒体损伤或自噬诱导之前。最后，贝伐单抗与葡萄糖摄取抑制剂的组合降低了体内肿瘤生长和血管生成，并改变了糖酵解蛋白的表达。总之，我们报道了贝伐单抗能够通过在体外消除自分泌VEGF来增加癌细胞上的葡萄糖代谢。在细胞水平上确定抗血管生成药物的作用可以使我们发现在未来恢复对这种治疗方法的获得性耐药性的方法。
Anti-VEGF therapy with Bevacizumab is approved for glioblastoma treatment, however, it is known that tumors acquired resistance and eventually became even more aggressive and infiltrative after treatment. In the present study we aimed to unravel the potential cellular mechanisms of resistance to Bevacizumab in glioblastoma in vitro models. Using a panel of glioblastoma cell lines we found that Bevacizumab is able to block the secreted VEGF by the tumor cells and be internalized to the cytoplasm, inducing cytotoxicity in vitro. We further found that Bevacizumab increases the expression of hypoxic (HIF-1α and CAIX) and glycolytic markers (GLUT1 and MCT1), leading to higher glucose uptake and lactate production. Furthermore, we showed that part of the consumed glucose by the tumor cells can be stored as glycogen, hampering cell dead following Bevacizumab treatment. Importantly, we found that this change on the glycolytic metabolism occurs independently of hypoxia and before mitochondrial impairment or autophagy induction. Finally, the combination of Bevacizumab with glucose uptake inhibitors decreased in vivo tumor growth and angiogenesis and shift the expression of glycolytic proteins. In conclusion, we reported that Bevacizumab is able to increase the glucose metabolism on cancer cells by abrogating autocrine VEGF in vitro. Define the effects of anti-angiogenic drugs at the cellular level can allow us to discover ways to revert acquired resistance to this therapeutic approaches in the future.
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影响因子：
11.2
作者：
Hu YL;DeLay M;Jahangiri A;Molinaro AM;Rose SD;Carbonell WS;Aghi MK
通讯作者：
Aghi MK
影响因子：
2.4
作者：
Hartwich, Joseph;Orr, W. Shannon;Ng, Catherine Y.;Spence, Yunyu;Morton, Christopher;Davidoff, Andrew M.
通讯作者：
Davidoff, Andrew M.
影响因子：
6.4
作者：
Hasan, Mohammad R.;Ho, Shirley H. Y.;Tai, Isabella T.
通讯作者：
Tai, Isabella T.
影响因子：
11.5
作者：
Guan, H;Jia, SF;Kleinerman, ES
通讯作者：
Kleinerman, ES
影响因子：
11.2
作者：
Curtarello, Matteo;Zulato, Elisabetta;Indraccolo, Stefano
通讯作者：
Indraccolo, Stefano