Understanding the Tumor Suppressor PTEN in Chronic Alcoholism and Hepatocellular Carcinoma

Shearn, Colin T.; Petersen, Dennis R.

doi:10.1007/978-3-319-09614-8_10

Cited by 27 publications

(23 citation statements)

References 66 publications

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“…Our previous work revealed that ethanol impaired the osteogenic differentiation of BMSCs via suppressing the Akt/GSK‐3β/β‐catenin pathway . In addition, PTEN expression is increased in alcohol‐consuming rats . Furthermore, the regulatory interaction between PTEN and the osteogenic response of bone tissue has been revealed by previous investigations .…”

Section: Discussionmentioning

confidence: 91%

Diminished membrane recruitment of Akt is instrumental in alcohol‐associated osteopenia via the PTEN/Akt/GSK‐3β/β‐catenin axis

et al. 2019

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Alcohol is considered a leading risk factor for osteopenia. Our previous research indicated that the Akt/GSK‐3β/β‐catenin pathway plays a critical role in the ethanol‐induced antiosteogenic effect in bone mesenchymal stem cells (BMSCs). PI3K/Akt is negatively regulated by the phosphatase and tensin homolog (PTEN) phosphatase. In this study, we found that ethanol increased PTEN expression in the BMSCs and bone tissue of ethanol‐treated Sprague–Dawley rats. PTEN upregulation impaired Akt recruitment to the plasma membrane and suppressed Akt phosphorylation at Ser473, thereby inhibiting Akt/GSK3β/β‐catenin signaling and the expression of COL1 and OCN in BMSCs in vitro and in vivo. The results of in vivo assays indicated that PTEN inhibition protected bone tissue against ethanol. Interestingly, our data revealed that following ethanol stimulation, PTEN and PTEN pseudogene 1 (PTENP1) mRNA expression was increased in a time‐dependent manner, resulting in an increased PTEN protein level. In addition, ethanol upregulated PTEN expression and decreased PTEN phosphorylation (p‐PTEN), indicating an increase in functional PTEN levels. In summary, the ethanol‐mediated transcriptional and post‐transcriptional regulation of PTEN impaired downstream Akt/GSK3β/β‐catenin signaling and BMSC osteogenic differentiation. Therefore, we propose that Akt/GSK3β/β‐catenin activation via PTEN inhibition may be a potential therapeutic approach for preventing the development of alcohol‐induced osteopenia.

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Section: Discussionmentioning

confidence: 91%

Diminished membrane recruitment of Akt is instrumental in alcohol‐associated osteopenia via the PTEN/Akt/GSK‐3β/β‐catenin axis

et al. 2019

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“…Akt is perhaps the most frequently activated oncoprotein in human cancers, and activation of Akt was implicated in the genesis of HCC (Moeini et al, 2012; Shearn and Petersen, 2015). Furthermore, hepatic deletion of Pten in mice induces HCC (Horie et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms

Wang

Chen

et al. 2016

Cancer Cell

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Summary Akt is frequently hyperactivated in human cancers and is targeted for cancer therapy. However, the physiological consequences of systemic Akt isoforms 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 develop 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 high incidence of lung metastasis. Thus, in contrast to other cancers, hepatic Akt inhibition induces liver injury that could promote HCC.

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“…In cancer biology, PTEN is frequently mutated or deleted in a wide variety of tumours. In patients with HCC, mutations, decreased promoter activity, and decreased PTEN expression are common occurrences . Indeed, the expression of PCAF increases the acetylation of lysine residues (Lys125 and 128) within the catalytic cleft of PTEN .…”

Section: Pcaf In Liver Cancer and Tumour Growthmentioning

confidence: 99%

PCAF fine‐tunes hepatic metabolic syndrome, inflammatory disease, and cancer

Yao

Shao

Zheng

et al. 2018

J Cellular Molecular Medi

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The P300/CBP‐associating factor (PCAF), a histone acetyltransferase, is involved in metabolic and pathogenic diseases, particularly of the liver. The effects of PCAF on fine‐tuning liver diseases are extremely complex and vary according to different pathological conditions. This enzyme has dichotomous functions, depending on differently modified sites, which regulate the activities of various enzymes, metabolic functions, and gene expression. Here, we summarize the most recent findings on the functions and targets of PCAF in various metabolic and immunological processes in the liver and review these new discoveries and models of PCAF biology in three areas: hepatic metabolic syndrome, inflammatory disease, and cancer. Finally, we discuss the potential implications of these findings for therapeutic interventions in liver diseases.

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Understanding the Tumor Suppressor PTEN in Chronic Alcoholism and Hepatocellular Carcinoma

Cited by 27 publications

References 66 publications

Diminished membrane recruitment of Akt is instrumental in alcohol‐associated osteopenia via the PTEN/Akt/GSK‐3β/β‐catenin axis

Diminished membrane recruitment of Akt is instrumental in alcohol‐associated osteopenia via the PTEN/Akt/GSK‐3β/β‐catenin axis

Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms

PCAF fine‐tunes hepatic metabolic syndrome, inflammatory disease, and cancer

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