Graff J R, De Benedetti A, Olson J W, Tamez P, Casero R A, Zimmer S G
Department of Microbiology and Immunology, L.P. Markey Cancer Center, University of Kentucky, Lexington 40536, USA.
Biochem Biophys Res Commun. 1997 Nov 7;240(1):15-20. doi: 10.1006/bbrc.1997.7592.
Rapid tumor growth and metastasis require increased polyamine metabolism, which is coordinately regulated by ornithine decarboxylase (ODC) and the polyamine transporter. Both activities are stimulated by ras signalling and are dependent upon protein biosynthesis. T24ras oncogene expression in rat embryo fibroblasts (CREFT24) induces cellular transformation and malignancy, in part, by stimulating the rate-limiting translation initiation factor, eIF-4E. CREFT24 expressing antisense RNA to eIF-4E (AS4E) have markedly decreased tumor growth rates and metastatic capacity, without altered monolayer growth rates. Herein, we demonstrate that in AS4E, ODC is translationally suppressed resulting in decreased ODC activity. Additionally, exogenous polyamine uptake is suppressed in AS4E cells indicating that AS4E can neither generate nor import the polyamines necessary to support rapid tumor growth. These data provide evidence that eIF-4E is the link between ras-induced malignancy and increased polyamine metabolism and support the hypothesis that eIF-4E plays a pivotal role in mediating ras-induced malignancy.
肿瘤的快速生长和转移需要多胺代谢增加，而多胺代谢由鸟氨酸脱羧酶（ODC）和多胺转运体协同调节。这两种活性均受ras信号传导刺激，且依赖于蛋白质生物合成。大鼠胚胎成纤维细胞（CREFT24）中T24ras癌基因的表达，部分通过刺激限速翻译起始因子eIF-4E诱导细胞转化和恶性肿瘤形成。表达针对eIF-4E的反义RNA（AS4E）的CREFT24细胞，其肿瘤生长速率和转移能力显著降低，而单层生长速率未改变。在此，我们证明在AS4E细胞中，ODC的翻译受到抑制，导致ODC活性降低。此外，AS4E细胞中外源多胺摄取受到抑制，这表明AS4E既不能产生也不能导入支持肿瘤快速生长所需的多胺。这些数据证明eIF-4E是ras诱导的恶性肿瘤与多胺代谢增加之间的联系，并支持eIF-4E在介导ras诱导的恶性肿瘤中起关键作用这一假说。
