Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms

Wang, Qi; Yu, Wan Ni; Chen, Xinyu; Peng, Xiao; Jeon, Sang‐Min; Birnbaum, Morris J.; Guzman, Grace; Hay, Nissim

doi:10.1016/j.ccell.2016.02.008

Cited by 93 publications

(103 citation statements)

References 43 publications

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“…Cellular mutations disrupt epithelial-barrier and compromise the basolateral cell polarity, thus promoting asymmetric cell division and oncogenic transformation leading to tumor initiation and growth[44]. These initiated tumor cells further undergo cellular transformations to attain invasive phenotype by shedding epithelial markers such as E-cadherins and keratins, and by gaining de novo mesenchymal markers such as N-cadherin, vimentin, snail1 etc[35]. This process known as EMT imparts the initiated cancer cells a spindle-shaped, motile and invasive mesenchymal phenotype that are a pre-requisite for cancer metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…In a TP53 R270H mouse model of prostate cancer, although the development of PIN was associated with increased Akt activation, invasive tumors indicated reduced Akt activation, suggesting that ‘Akt de-addiction’ may be necessary for attaining invasive ability[34]. Very recently, Akt1 −/− /Akt2 −/− mice exhibited enhanced growth and metastasis in a drug-induced liver cancer model[35]. Thus, the increasing number of recent evidence suggests a context specific, the dual function of Akt in the early and advanced cancers.…”

Section: Introductionmentioning

confidence: 99%

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Suppression of Akt1-β-catenin pathway in advanced prostate cancer promotes TGFβ1-mediated epithelial to mesenchymal transition and metastasis

et al. 2017

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Akt1 is essential for the oncogenic transformation and tumor growth in various cancers. However, the precise role of Akt1 in advanced cancers is conflicting. Using a neuroendocrine TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, we first show that the genetic ablation or pharmacological inhibition of Akt1 in mice blunts oncogenic transformation and prostate cancer (PCa) growth. Intriguingly, triciribine (TCBN)-mediated Akt inhibition in 25-week old, tumor-bearing TRAMP mice and Akt1 gene silencing in aggressive PCa cells enhanced epithelial to mesenchymal transition (EMT) and promoted metastasis to the lungs. Mechanistically, Akt1 suppression leads to increased expression of EMT markers such as Snail1 and N-cadherin and decreased expression of epithelial marker E-cadherin in TRAMP prostate, and in PC3 and DU145 cells. Next, we identified that Akt1 knockdown in PCa cells results in increased production of TGFβ1 and its receptor TGFβ RII, associated with a decreased expression of β-catenin. Furthermore, treatment of PCa cells with ICG001 that blocks nuclear translocation of β-catenin promoted EMT and N-cadherin expression. Together, our study demonstrates a novel role of the Akt1-β-catenin-TGFβ1 pathway in advanced PCa.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Suppression of Akt1-β-catenin pathway in advanced prostate cancer promotes TGFβ1-mediated epithelial to mesenchymal transition and metastasis

et al. 2017

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“…Although hyperactivation of Akt is frequently detected in human cancers and is therefore a therapeutic target, hepatic deletion of Akt1 in Akt2 −/− mice surprisingly triggered spontaneous HCC development (Wang et al, 2016). Given the bidirectional roles of these signaling molecules in liver tumorigenesis and the disappointing therapeutic effect of Sorafenib, we propose here that targeting further downstream and signal-culminating molecules may be a more efficient pharmaceutical means for treatment of liver cancer.…”

Section: Discussionmentioning

confidence: 99%

Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells

et al. 2016

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SUMMARY The complexity of liver tumorigenesis is underscored by the recently observed anti-oncogenic effects of oncoproteins, although the mechanisms are unclear. Shp2/Ptpn11 is a proto-oncogene in hematopoietic cells, and antagonizes the effect of tumor suppressor Pten in leukemogenesis. In contrast, we show here cooperative functions of Shp2 and Pten in suppressing hepatocarcinogenesis. Ablating both Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH), and promoted genesis of liver tumor-initiating cells likely due to augmented cJun expression/activation, and elevated ROS and inflammation in the hepatic microenvironment. Inhibiting cJun partially suppressed NASH-driven liver tumorigenesis without improving NASH. SHP2 and PTEN deficiencies were detected in liver cancer patients with poor prognosis. These data depict a mechanism of hepato-oncogenesis and suggest a potential therapeutic strategy.

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“…Finally, in diethylnitrosamine (DEN)-treated mice, a model of HCC, the incidence of lung metastasis was markedly increased in Akt2 −/− but not Akt1 −/− mice. Again, this phenomenon could be attributed to the very high level of insulin in Akt2-deficient mice (Wang et al , 2016). …”

Section: The Consequences Of Systemic Akt Gene Deletion In Adult Micementioning

confidence: 99%

Akt as a target for cancer therapy: more is not always better (lessons from studies in mice)

2017

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The PI3K/Akt signalling pathway is one of the most frequently altered signalling networks in human cancers and has become an attractive target in anticancer therapy. Several drugs targeting this pathway are currently in different phases of clinical trials. However, accumulating reports suggest that adverse effects such as hyperglycaemia and hyperinsulinaemia accompany treatment with pan-PI3K and pan-Akt inhibitors. Thus, understanding the consequences of the systemic deletion or inhibition of Akt activity in vivo is imperative. Three Akt isoforms may individually affect different cancer cells in culture to varying degrees that could suggest specific targeting of different Akt isoforms for different types of cancer. However, the results obtained in cell culture do not address the consequences of Akt isoform inhibition at the organismal level and consequently fail to predict the feasibility of targeting these isoforms for cancer therapy. This review summarises and discusses the consequences of genetic deletions of Akt isoforms in adult mice and their implications for cancer therapy. Whereas combined Akt1 and Akt2 rapidly induced mortality, hepatic Akt inhibition induced liver injury that promotes hepatocellular carcinoma. These findings may explain some of the side effects exerted by pan-PI3K and pan-Akt inhibitors and suggest that close attention must be paid when targeting all Akt isoforms as a therapeutic intervention.

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Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms

Cited by 93 publications

References 43 publications

Suppression of Akt1-β-catenin pathway in advanced prostate cancer promotes TGFβ1-mediated epithelial to mesenchymal transition and metastasis

Suppression of Akt1-β-catenin pathway in advanced prostate cancer promotes TGFβ1-mediated epithelial to mesenchymal transition and metastasis

Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells

Akt as a target for cancer therapy: more is not always better (lessons from studies in mice)

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