Mechanism of rapamycin-resistant translation in mouse hepatocellular carcinoma cells

在小鼠肝癌发生过程中，PI3K-Akt-mTOR通路激活了蛋白质的翻译，但mTOR抑制剂雷帕霉素对肝细胞癌的抗肿瘤作用有限，对肝腺瘤无作用，尽管雷帕霉素抑制了帽依赖的蛋白质翻译。在雷帕霉素作用下，HIF-1α可以通过内部核糖体进入位点机制继续表达。此外，雷帕霉素诱导肿瘤坏死的机制不是由于对肝癌细胞的直接作用，而是由于雷帕霉素对肝癌血管系统的血管毒性作用。

Although protein translation is activated by the PI3K-Akt-mTOR pathway in mouse hepatocarcinogenesis, rapamycin, a mTOR inhibitor, shows the limited antitumor effect on hepatocellular carcinomas and no effect on hepatic adenomas despite the fact that the cap-dependent protein translation is inhibited by rapamycin. Under the condition with rapamycin treatment, HIF-1α can continue to be expressed by the internal ribosomal entry site (IRES) mechanism. Furthermore, the mechanism of tumor necrosis induced by rapamycin was not due to the direct action against hepatocellular carcinoma cells but rather due to the angiotoxic effect of rapamycin against the vasculature of hepatocellular carcinomas.