Arif Tasleem, Paul Avijit, Krelin Yakov, Shteinfer-Kuzmine Anna, Shoshan-Barmatz Varda
Department of Life Sciences, The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Cancers (Basel). 2018 Dec 8;10(12):499. doi: 10.3390/cancers10120499.
Oncogenic properties, along with the metabolic reprogramming necessary for tumour growth and motility, are acquired by cancer cells. Thus, tumour metabolism is becoming a target for cancer therapy. Here, cancer cell metabolism was tackled by silencing the expression of voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein that controls cell energy, as well as metabolic and survival pathways and that is often over-expressed in many cancers. We demonstrated that silencing VDAC1 expression using human-specific siRNA (si-hVDAC1) inhibited cancer cell growth, both in vitro and in mouse xenograft models of human glioblastoma (U-87MG), lung cancer (A549), and triple negative breast cancer (MDA-MB-231). Importantly, treatment with si-hVDAC1 induced metabolic rewiring of the cancer cells, reversing their oncogenic properties and diverting them towards differentiated-like cells. The si-hVDAC1-treated residual "tumour" showed reprogrammed metabolism, decreased proliferation, inhibited stemness and altered expression of genes and proteins, leading to cell differentiation toward less malignant lineages. These VDAC1 depletion-mediated effects involved alterations in master transcription factors associated with cancer hallmarks, such as highly increased expression of p53 and decreased expression of HIF-1a and c-Myc that regulate signalling pathways (e.g., AMPK, mTOR). High expression of p53 and the pro-apoptotic proteins cytochrome c and caspases without induction of apoptosis points to functions for these proteins in promoting cell differentiation. These results clearly show that VDAC1 depletion similarly leads to a rewiring of cancer cell metabolism in breast and lung cancer and glioblastoma, regardless of origin or mutational status. This metabolic reprogramming results in cell growth arrest and inhibited tumour growth while encouraging cell differentiation, thus generating cells with decreased proliferation capacity. These results further suggest VDAC1 to be an innovative and markedly potent therapeutic target.
癌细胞获得了致癌特性以及肿瘤生长和迁移所必需的代谢重编程。因此，肿瘤代谢正成为癌症治疗的一个靶点。在此，通过沉默电压依赖性阴离子通道1（VDAC1）的表达来研究癌细胞代谢，VDAC1是一种线粒体蛋白，可控制细胞能量以及代谢和生存途径，并且在许多癌症中经常过度表达。我们证明，使用人特异性小干扰RNA（si-hVDAC1）沉默VDAC1表达可在体外以及人胶质母细胞瘤（U-87MG）、肺癌（A549）和三阴性乳腺癌（MDA-MB-231）的小鼠异种移植模型中抑制癌细胞生长。重要的是，用si-hVDAC1处理可诱导癌细胞的代谢重排，逆转其致癌特性并使其向类似分化细胞转变。经si-hVDAC处理的残留“肿瘤”显示出代谢重编程、增殖减少、干性抑制以及基因和蛋白质表达改变，导致细胞向恶性程度较低的谱系分化。这些VDAC1缺失介导的效应涉及与癌症特征相关的主要转录因子的改变，例如p53表达高度增加以及调节信号通路（如AMPK、mTOR）的HIF-1α和c-Myc表达降低。p53以及促凋亡蛋白细胞色素c和半胱天冬酶的高表达而未诱导细胞凋亡表明这些蛋白在促进细胞分化中发挥作用。这些结果清楚地表明，无论起源或突变状态如何，VDAC1缺失同样会导致乳腺癌、肺癌和胶质母细胞瘤中癌细胞代谢的重排。这种代谢重编程导致细胞生长停滞和肿瘤生长受抑制，同时促进细胞分化，从而产生增殖能力降低的细胞。这些结果进一步表明VDAC1是一个创新且极具潜力的治疗靶点。
