Abstract
Akt is frequently hyperactivated in human cancers and is targeted for cancer therapy. However, the physiological consequences of systemic Akt isoform inhibition were not fully explored. We showed that while combined Akt1 and Akt3 deletion in adult mice is tolerated, combined Akt1 and Akt2 deletion induced rapid mortality. Akt2(-/-) mice survived hepatic Akt1 deletion but all developed spontaneous hepatocellular carcinoma (HCC), which is associated with FoxO-dependent liver injury and inflammation. The gene expression signature of HCC-bearing livers is similar to aggressive human HCC. Consistently, neither Akt1(-/-) nor Akt2(-/-) mice are resistant to diethylnitrosamine-induced hepatocarcinogenesis, and Akt2(-/-) mice display a high incidence of lung metastasis. Thus, in contrast to other cancers, hepatic Akt inhibition induces liver injury that could promote HCC.
Copyright © 2016 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Comment
MeSH terms
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Age Factors
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Animals
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Blood Glucose / analysis
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Energy Metabolism / genetics
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Fatty Acids / metabolism
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Female
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Forkhead Box Protein O1
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Forkhead Transcription Factors / physiology
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Growth Disorders / genetics
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Hepatitis / genetics
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Hypoglycemia / genetics
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Insulin / blood
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Insulin Resistance
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Interleukin-6 / blood
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Liver Neoplasms, Experimental / chemically induced
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Liver Neoplasms, Experimental / genetics*
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Lung Neoplasms / secondary
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Male
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Mice
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Mice, Knockout
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Promoter Regions, Genetic / drug effects
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Protein Isoforms / physiology
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Proto-Oncogene Proteins c-akt / deficiency*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / physiology
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Recombinant Fusion Proteins / metabolism
Substances
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Blood Glucose
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Fatty Acids
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Foxo1 protein, mouse
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Insulin
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Interleukin-6
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Protein Isoforms
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Recombinant Fusion Proteins
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interleukin-6, mouse
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Akt1 protein, mouse
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Akt2 protein, mouse
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Akt3 protein, mouse
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Proto-Oncogene Proteins c-akt