Mechanism of rapamycin-resistant translation in mouse hepatocellular carcinoma cells

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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.