The anticancer gene ORCTL3 targets stearoyl-CoA desaturase-1 for tumour-specific apoptosis.
The anticancer gene ORCTL3 targets stearoyl-CoA desaturase-1 for tumour-specific apoptosis.
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ORCTL3是一组基因的成员，所谓的抗癌基因，导致肿瘤特异性细胞死亡。我们发现，这种活性在等基因肾细胞的转化过程中被触发，而与细胞的增殖状态无关。ORCTL3具有细胞死亡作用，靶向脂肪酸代谢中的硬脂酰辅酶a去饱和酶-1 （SCD1）。这是由跨膜结构域3和4引起的，它们在体外比低分子量药物对SCD1更有效，并且严重依赖于它们的表达水平。发现SCD1在肾细胞转化过程中上调，表明其活性虽然不影响增殖，但却是肿瘤发生的关键瓶颈。一种表达ORCTL3的腺病毒在体内抑制肾肿瘤的生长，并在体外大量破坏患者的肾肿瘤细胞。我们的研究结果表明，脂肪酸代谢是肾肿瘤中肿瘤特异性凋亡的一个靶点，并建议ORCTL3作为实现这一目标的一种手段。
ORCTL3 is a member of a group of genes, the so-called anticancer genes, that cause tumour-specific cell death. We show that this activity is triggered in isogenic renal cells upon their transformation independently of the cells’ proliferation status. For its cell death effect ORCTL3 targets the enzyme stearoyl-CoA desaturase-1 (SCD1) in fatty acid metabolism. This is caused by transmembrane domains 3 and 4, which are more efficacious in vitro than a low molecular weight drug against SCD1, and critically depend on their expression level. SCD1 is found upregulated upon renal cell transformation indicating that its activity, while not impacting proliferation, represents a critical bottleneck for tumourigenesis. An adenovirus expressing ORCTL3 leads to growth inhibition of renal tumours in vivo and to substantial destruction of patients’ kidney tumour cells ex vivo. Our results indicate fatty acid metabolism as a target for tumour-specific apoptosis in renal tumours and suggest ORCTL3 as a means to accomplish this.
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64.8
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Navin N;Kendall J;Troge J;Andrews P;Rodgers L;McIndoo J;Cook K;Stepansky A;Levy D;Esposito D;Muthuswamy L;Krasnitz A;McCombie WR;Hicks J;Wigler M
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