Functional crosstalk between AKT/mTOR and Ras/MAPK pathways in hepatocarcinogenesis: Implications for the treatment of human liver cancer

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, with limited treatment options. AKT/mTOR and Ras/MAPK pathways are frequently deregulated in human hepatocarcinogenesis. Recently, we generated an animal model characterized by the co-expression of activated forms of AKT and Ras in the mouse liver. We found that concomitant activation of AKT/mTOR and Ras/MAPK cascades leads to rapid liver tumor development in AKT/Ras mice, mainly through mTORC1 induction. To further define the role of mTORC1 cascade in AKT/Ras induced HCC development, the mTORC1 inhibitor Rapamycin was administered to AKT/Ras mice at the time when small tumors started to emerge in the liver. Of note, Rapamycin treatment significantly delayed hepatocarcinogenesis in AKT/Ras mice. However, some microscopic lesions persisted in the livers of AKT/Ras mice despite the treatment and rapidly gave rise to HCC following Rapamycin withdrawal. Mechanistically, Rapamycin inhibited mTORC1 and mTORC2 pathways, lipogenesis and glycolysis, resulting in inhibition of proliferation in the treated livers. However, activated ERK and its downstream effectors, Mnk1 and eIF4E, were strongly upregulated in the residual lesions. Concomitant suppression of AKT/mTOR and Ras/MAPK pathways was highly detrimental for the growth of AKT/Ras cells in vitro. The study indicates the existence of a complex interplay between AKT/mTOR and Ras/MAPK pathways during hepatocarcinogenesis, with important implications for the understanding of HCC pathogenesis as well as for its prevention and treatment.

Current treatment strategies for inhibiting mTOR in cancer

“…In particular, ERK phosphorylates mitogen-activated protein kinase-interacting kinase (Mnk) 1 and 2, which are upstream of eIF4E [60]. Moreover, it is interesting that Mnk 1/2 activation has been detected both in vitro and in vivo in xenograft models, in response to tumor cell treatment with rapamycin, and that cotreatment with an Mnk 1/2 inhibitor potentiated the antineoplastic activity of rapamycin [61,62]. eIF4B significantly increases the helicase activity of eIF4A, which unwinds the secondary structure of the 5 0 untranslated region (UTR), allowing the 40S ribosomal subunit to bind to the mRNA [63].…”

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

“…Therefore, better survival outcomes may be achieved by using promising combinations of targeted therapies through inhibiting different pathways involved in HCC. Ras/MAPK and AKT/mTOR pathways are frequently deregulated in human hepatocarcinogenesis [141]. The combination of PKI-587, targeting PI3K/AKT/mTOR pathway and sorafenib, mainly targeting Ras/ Raf/MAPK signaling pathways, has the advantage over monodrug therapy on inhibition of HCC cell proliferation by blocking both the signaling pathways simultaneously [142].…”

Crosstalk analysis of pathways in breast cancer using a network model based on overlapping differentially expressed genes

“…The study conducted by Krysan et al (15) indicated that PGE2 was able to induce the proliferation of colon and lung cancer cells through the activation of MAPK in an EGFR-independent manner in vitro. Wang et al (16) generated a mouse model characterized by the co-expression of activated forms of AKT and Ras in the liver. The results indicated that concomitant suppression of AKT/mTOR and Ras/MAPK pathways was highly detrimental for the growth of AKT/Ras-expressing cells in vitro.…”