Hepatic Deletion of AKT1 and AKT2 Induces Hepatocellular Carcinoma

The serine/threonine AKT family kinases (AKT1, AKT2, and AKT3) are frequently activated in cancer, and pan-AKT inhibitors are in clinical trials, making it important to understand the systemic effects of deletion of each isoform. Wang, Yu, and colleagues characterized systemic combined deletion of Akt isoforms in adult mice. While inducible deletion of Akt1 in an Akt3 null background was tolerated, combined systemic deletion of Akt1 and Akt2 was toxic and led to inflammation, hypoglycemic shock, and death. Hepatic deletion of Akt1 in Akt2-null mice was tolerated, but the mice exhibited reduced body weight and developed spontaneous hepatocellular carcinoma (HCC). The initiation of liver carcinogenesis is often associated with liver injury and inflammation. Consistent with this observation, hepatic deletion of Akt1 in Akt2-null mice led to increased serum levels of injury-associated liver enzymes and inflammatory markers, such as interleukin-6 (IL6) and tumor necrosis factor alpha (TNFα). Hepatic tumor sections were characterized by increased proliferation and macrophage infiltration. Mechanistically, inflammation in Akt1/Akt2-deleted livers was driven by FOXO1-mediated transcription, and subsequent deletion of FOXO1 reversed liver inflammation and tumorigenesis in the context of Akt1/Akt2 loss. Increased IL6 production and high levels of protumorigenic STAT3 signaling were observed within tumor-associated hepatocytes, and RNA sequencing revealed an upregulation of gene signatures associated with aggressive human hepatocellular carcinoma. Although deletion of either Akt1 or Akt2 alone did not inhibit carcinogen-induced HCC, Akt2 deletion contributed to increased lung metastasis originating from primary liver tumors. Together, these data show that while systemic loss of AKT1 and AKT2 is lethal, hepatic deletion of the two AKT isoforms accelerates hepatocarcinogenesis due to FOXO1-driven liver injury and inflammation, and suggest a need for AKT isoform–specific inhibitors, which may be better tolerated than pan-AKT inhibitors and prevent liver damage and inflammation.

Wang Q, Yu W-N, Chen X, Peng X-d, Jeon S-M, Birnbaum MJ, et al. Spontaneous hepatocellular carcinoma after the combined deletion of Akt isoforms. Cancer Cell 2016 Mar 17 [Epub ahead of print].

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