Downregulation of voltage-dependent anion channel-1 expression by RNA interference prevents cancer cell growth in vivo
Downregulation of voltage-dependent anion channel-1 expression by RNA interference prevents cancer cell growth in vivo
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DOI：
10.4161/cbt.9.12.11879
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发表时间：
2010-06-15
影响因子：
3.6
通讯作者：
Shoshan-Barmatz, Varda
中科院分区：
文献类型：
--
作者：
Koren, Inbar;Raviv, Ziv;Shoshan-Barmatz, Varda
电压依赖性阴离子通道1（VDAC 1）位于线粒体外膜（OMM），是调节离子、核苷酸和多种代谢物在线粒体内外交换的关键蛋白。因此，VDAC在细胞能量维持中起着至关重要的作用。我们之前已经证明，通过使用针对人（h）VDAC 1的shRNA进行RNA干扰，使T-Rex-293细胞中的VDAC 1表达沉默，导致ATP产生减少和细胞生长减少。由于癌细胞高度表达VDAC，我们在此研究了shRNA-hVDAC 1介导的VDAC 1表达沉默对动物模型中癌细胞生长的影响。为此，用编码针对hVDAC 1的序列的诱导型shRNA质粒稳定转染HeLa宫颈癌细胞。这些细胞中的VDAC 1表达几乎完全降低。稳定转染的shRNA-hVDAC 1 HeLa细胞增殖比对照细胞慢得多，表明VDAC 1表达对于HeLa癌细胞的正常生长是必不可少的。我们进一步研究了hVDAC 1沉默在体内阻断癌细胞增殖的能力。皮下接种稳定转染shRNA-hVDAC 1 HeLa细胞的裸鼠产生的肿瘤比接种对照HeLa细胞的小鼠小约40倍。总之，这项研究的结果首次证明了通过shRNA下调VDAC 1的抗癌治疗潜力。
The voltage-dependent anion channel 1 (VDAC1), located at the outer mitochondrial membrane (OMM), is a key protein in regulating the exchange of ions, nucleotides and a variety of metabolites in and out of the mitochondria. As such, VDAC serves a crucial role in cellular energy maintenance. We have previously shown that silencing VDAC1 expression in T-Rex-293 cells by means of RNA interference using shRNA directed to human (h) VDAC1 resulted in reduced ATP production and a decrease in cell growth. Since cancer cells highly express VDAC, we examined here the effects of shRNA-hVDAC1-mediated silencing of VDAC1 expression on cancer cell growth in an animal model. To this end, HeLa cervical cancer cells were stably transfected with an inducible shRNA plasmid encoding for a sequence directed to hVDAC1. VDAC1 expression in these cells was decreased almost completely. Stably transfected shRNA-hVDAC1 HeLa cells proliferated much slower than did control cells, pointing to VDAC1 expression as being essential for normal growth of HeLa cancer cells. We further studied the ability of hVDAC1 silencing to block cancer cell proliferation in vivo. Nude mice subcutaneously inoculated with stably transfected shRNA-hVDAC1 HeLa cells developed about 40-fold smaller tumors than did mice inoculated with control HeLa cells. Taken together, the results of this study demonstrate, for the first time, the anticancer therapeutic potential of VDAC1 downregulation by means of shRNA.