4EBP1/eIF4E and p70S6K/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N-Ras protooncogenes in mice

Abstract

Concomitant expression of activated forms of AKT and Ras in the mouse liver (AKT/Ras) leads to rapid tumor development via strong activation of the mTORC1 pathway. mTORC1 functions via regulating p70S6K/RPS6 and 4EBP1/eIF4E cascades. How these cascades contribute to hepatocarcinogenesis remains unknown. Here, we show that inhibition of RPS6 pathway via Rapamycin effectively suppressed, whereas blockade of the 4EBP1/eIF4E cascade by 4EBP1A4, an unphosphorylatable form of 4EBP1, significantly delayed, AKT/Ras induced hepatocarcinogenesis. Combined treatment with Rapamycin and 4EBP1A4 completely inhibited AKT/Ras hepatocarcinogenesis. This strong anti-neoplastic effect was successfully recapitulated by ablating Raptor, the major subunit of mTORC1, in AKT/Ras-overexpressing livers. Furthermore, we demonstrate that overexpression of eIF4E, the protooncogene whose activity is specifically inhibited by 4EBP1, resulted in HCC development in cooperation with activated Ras. Mechanistically, we identified the ENTPD5/AK1/CMPK1 axis and the mitochondrial biogenesis pathway as targets of the 4EBP1/eIF4E cascade in AKT/Ras and Ras/eIF4E livers as well as in human HCC cell lines and tissues. Conclusions: Complete inhibition of mTORC1 is required to suppress liver cancer development induced by AKT and Ras protooncogenes in mice. The mTORC1 effectors, RPS6 and eIF4E, play distinct roles and are both necessary for AKT/Ras hepatocarcinogenesis. These new findings might open the way for innovative therapies against human hepatocellular carcinoma.