title: V-AKT murine thymoma viral oncogene homolog/mammalian target of rapamycin activation induces a module of metabolic changes contributing to growth in insulin-induced hepatocarcinogenesis.
abstract: Mounting epidemiological evidence supports a role for insulin-signaling deregulation and diabetes mellitus in human hepatocarcinogenesis. However, the underlying molecular mechanisms remain unknown. To study the oncogenic effect of chronically elevated insulin on hepatocytes in the presence of mild hyperglycemia, we developed a model of pancreatic islet transplantation into the liver. In this model, islets of a donor rat are transplanted into the liver of a recipient diabetic rat, with resulting local hyperinsulinism that leads to the development of preneoplastic lesions and hepatocellular carcinoma (HCC). Here, we investigated the metabolic and growth properties of the v-akt murine thymoma viral oncogene homolog/mammalian target of rapamycin (AKT/mTOR) pathway, a major downstream effector of insulin signaling, in this model of insulin-induced hepatocarcinogenesis. We found that activation of insulin signaling triggers a strong induction of the AKT/mTOR cascade that is paralleled by increased synthesis of fatty acids, cholesterol, and triglycerides, induction of glycolysis, and decrease of fatty acid oxidation and gluconeogenesis in rat preneoplastic and neoplastic liver lesions, when compared with the healthy liver. AKT/mTOR metabolic effects on hepatocytes, after insulin stimulation, were found to be mTORC1 dependent and independent in human HCC cell lines. In these cells, suppression of lipogenesis, glycolysis, and the pentose phosphate pathway triggered a strong growth restraint, despite insulin administration. Noticeably, metabolic abnormalities and proliferation driven by insulin were effectively reverted using the dual PI3K/mTOR inhibitor, NVP-BEZ235, both in vitro and in vivo.
  
  
  CONCLUSIONS
  The present results indicate that activation of the AKT/mTOR cascade by unconstrained insulin signaling induces a defined module of metabolic alterations in hepatocytes contributing to aberrant cell growth. Thus, inhibition of AKT/mTOR and related metabolic changes might represent a novel preventive and therapeutic approach to effectively inhibit insulin-induced hepatocarcinogenesis.
authors.affiliation: Institut für Pathologie, Ernst-Moritz-Arndt-Universität, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.forename: Katja
authors.initials: K
authors.lastname: Evert
authors.forename: Valentina
authors.initials: V
authors.lastname: De Murtas
authors.forename: Gioia
authors.initials: G
authors.lastname: Gasparetti
authors.forename: Sandra
authors.initials: S
authors.lastname: Mattu
authors.forename: Giulia
authors.initials: G
authors.lastname: Destefanis
authors.forename: Sara
authors.initials: S
authors.lastname: Ladu
authors.forename: Antje
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Salvatore
authors.initials: S
authors.lastname: Delogu
authors.forename: Sara
authors.initials: S
authors.lastname: Thiel
authors.forename: Andrea
authors.initials: A
authors.lastname: Thiele
authors.forename: Silvia
authors.initials: S
authors.lastname: Ribback
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D006946:Hyperinsulinism / Q000503:physiopathology*; D015151:Immunoblotting; D050155:Lipogenesis / Q000187:drug effects; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D012680:Sensitivity and Specificity; D020123:Sirolimus / Q000494:pharmacology*; D013311:Streptozocin / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013945:Thymoma / Q000821:virology; D014162:Transfection
chemical_list: D005227:Fatty Acids; D013311:Streptozocin; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus