title: 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.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.forename: Antonio
authors.initials: A
authors.lastname: Cigliano
authors.forename: Salvatore
authors.initials: S
authors.lastname: Delogu
authors.forename: Julia
authors.initials: J
authors.lastname: Armbruster
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020239:Receptor Cross-Talk; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; D020123:Sirolimus