VDAC1 is a molecular target in glioblastoma, with its depletion leading to reprogrammed metabolism and reversed oncogenic properties
VDAC1 is a molecular target in glioblastoma, with its depletion leading to reprogrammed metabolism and reversed oncogenic properties
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DOI：
10.1093/neuonc/now297
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发表时间：
2017-07-01
期刊：
影响因子：
15.9
通讯作者：
Shoshan-Barmatz, Varda
中科院分区：
文献类型：
--
作者：
Arif, Tasleem;Krelin, Yakov;Shoshan-Barmatz, Varda
背景胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，复发率高，死亡率高，目前仍有待有效的治疗。像许多癌症一样，GBM细胞获得致癌特性，包括对生长至关重要的代谢重编程。因此，肿瘤代谢是癌症治疗的新兴途径。一个相关的目标是电压依赖性阴离子通道1（VDAC 1），一种控制细胞能量和代谢稳态的线粒体蛋白。我们使用VDAC 1特异性短干扰（si）RNA（si-VDAC 1）处理GBM细胞系和皮下或颅内原位GBM异种移植小鼠模型。采用MRI、免疫组化、免疫印迹、免疫荧光、实时定量PCR、转录因子表达和DNA微阵列分析监测肿瘤。在9种胶质母细胞瘤相关细胞系（包括患者来源的细胞）中使用si-VDAC 1沉默VDAC 1表达，导致VDAC 1水平和细胞生长显著降低。在皮下或颅内原位GBM模型中使用si-VDAC 1可抑制肿瘤生长并逆转致癌特性，如重编程代谢、干性、血管生成、上皮-间充质转化和侵袭性。在培养的细胞中，siVDAC 1抑制癌症神经球的形成，并在肿瘤中靶向癌症干细胞，导致其分化为神经元样细胞。这些VDAC 1缺失介导的效应涉及调节与癌症标志物相关的信号通路的转录因子的改变。VDAC 1为GBM治疗提供了一个靶点，允许攻击代谢和致癌信号网络之间的相互作用，导致肿瘤细胞分化为神经元和星形胶质细胞样细胞。在攻击所有这些过程的同时，VDAC 1耗尽克服了GBM异质性，并可以取代几种分别靶向血管生成，增殖或代谢的抗癌药物。
Background. Glioblastoma (GBM), an aggressive brain tumor with frequent relapses and a high mortality, still awaits an effective treatment. Like many cancers, GBM cells acquire oncogenic properties, including metabolic reprogramming, vital for growth. As such, tumor metabolism is an emerging avenue for cancer therapy. One relevant target is the voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein controlling cell energy and metabolic homeostasis.Methods. We used VDAC1-specific short interfering (si) RNA (si-VDAC1) to treat GBM cell lines and subcutaneous or intracranial-orthotopic GBM xenograft mouse models. Tumors were monitored using MRI, immunohistochemistry, immunoblotting, immunofluorescence, quantitative real-time PCR, transcription factor expression, and DNA microarray analyses.Results. Silencing VDAC1 expression using si-VDAC1 in 9 glioblastoma-related cell lines, including patient-derived cells, led to marked decreases in VDAC1 levels and cell growth. Using si-VDAC1 in subcutaneous or intracranial-orthotopic GBM models inhibited tumor growth and reversed oncogenic properties, such as reprogrammed metabolism, stemness, angiogenesis, epithelial-mesenchymal transition, and invasiveness. In cells in culture, siVDAC1 inhibits cancer neurosphere formation and, in tumors, targeted cancer stem cells, leading to their differentiation into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks.Conclusion. VDAC1 offers a target for GBM treatment, allowing for attacks on the interplay between metabolism and oncogenic signaling networks, leading to tumor cell differentiation into neuron- and astrocyte-like cells. Simultaneously attacking all of these processes, VDAC1 depletion overcame GBM heterogeneity and can replace several anticancer drugs that separately target angiogenesis, proliferation, or metabolism.