电压依赖性阴离子通道 1（VDAC1）是神经胶质瘤的一个分子靶标，其耗竭导致代谢重编程和致癌特性逆转。
VDAC1 is a molecular target in glioblastoma, with its depletion leading to reprogrammed metabolism and reversed oncogenic properties.
机构信息
Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev,Beer-Sheva, Israel; Department of Pathology, Soroka University Medical Centre, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
出版信息
Neuro Oncol. 2017 Jul 1;19(7):951-964. doi: 10.1093/neuonc/now297.
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, si-VDAC1 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.
背景
胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，频繁复发且死亡率高，目前仍缺乏有效的治疗方法。与许多癌症一样，GBM 细胞获得致癌特性，包括代谢重编程，这对生长至关重要。因此，肿瘤代谢是癌症治疗的一个新兴途径。一个相关的靶点是电压依赖性阴离子通道 1（VDAC1），一种控制细胞能量和代谢平衡的线粒体蛋白。
方法
我们使用 VDAC1 特异性小干扰 (si)RNA（si-VDAC1）治疗 GBM 细胞系和皮下或颅内原位 GBM 异种移植小鼠模型。使用 MRI、免疫组织化学、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。
结果
在 9 种与胶质母细胞瘤相关的细胞系中，包括源自患者的细胞，使用 si-VDAC1 沉默 VDAC1 表达导致 VDAC1 水平和细胞生长明显下降。在皮下或颅内原位 GBM 模型中使用 si-VDAC1 抑制肿瘤生长并逆转致癌特性，如重编程代谢、干细胞特性、血管生成、上皮-间充质转化和侵袭性。在细胞培养中，si-VDAC1 抑制癌症神经球形成，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 VDAC1 耗竭介导的效应涉及调节与癌症特征相关信号通路的转录因子的改变。
结论
VDAC1 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样细胞和星形胶质细胞样细胞。同时攻击所有这些过程，VDAC1 耗竭克服了 GBM 的异质性，可以替代分别靶向血管生成、增殖或代谢的几种抗癌药物。
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