title: 4EBP1/eIF4E and p70S6K/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N-Ras proto-oncogenes in mice.
abstract: Concomitant expression of activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and Ras in mouse liver (AKT/Ras) leads to rapid tumor development through strong activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. mTORC1 functions by regulating p70S6K/ribosomal protein S6 (RPS6) and eukaryotic translation initiation factor 4E-binding protein 1/ eukaryotic translation initiation factor 4E (4EBP1/eIF4E) cascades. How these cascades contribute to hepatocarcinogenesis remains unknown. Here, we show that inhibition of the RPS6 pathway by 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 antineoplastic effect was successfully recapitulated by ablating regulatory associated protein of mTORC1, the major subunit of mTORC1, in AKT/Ras-overexpressing livers. Furthermore, we demonstrate that overexpression of eIF4E, the proto-oncogene whose activity is specifically inhibited by 4EBP1, resulted in hepatocellular carcinoma (HCC) development in cooperation with activated Ras. Mechanistically, we identified the ectonucleoside triphosphate diphosphohydrolase 5/ adenylate kinase 1/cytidine monophosphate kinase 1 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 proto-oncogenes 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 HCC.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.forename: Antonio
authors.initials: A
authors.lastname: Cigliano
authors.forename: Lijie
authors.initials: L
authors.lastname: Jiang
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Li
authors.forename: Biao
authors.initials: B
authors.lastname: Fan
authors.forename: Maria G
authors.initials: MG
authors.lastname: Pilo
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Bing
authors.initials: B
authors.lastname: Gui
authors.forename: Marcella
authors.initials: M
authors.lastname: Sini
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Smith
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D011755:Pyrophosphatases / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; C000715470:MAS1 protein, human; D046912:Multiprotein Complexes; D015513:Oncogene Proteins; D010750:Phosphoproteins; D000090063:Proto-Oncogene Mas; D038601:Ribosomal Protein S6; C448579:ribosomal protein S6, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C117634:ENTPD5 protein, human; D011755:Pyrophosphatases; D016283:Proto-Oncogene Proteins p21(ras); D020123:Sirolimus