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BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer
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BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer
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Journal Article
BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer
2020
Overview
Background
3-Hydroxy butyrate dehydrogenase 2 (BDH2) is a short-chain dehydrogenase/reductase family member that plays a key role in the development and pathogenesis of human cancers. However, the role of BDH2 in gastric cancer (GC) remains largely unclear. Our study aimed to ascertain the regulatory mechanisms of BDH2 in GC, which could be used to develop new therapeutic strategies.
Methods
Western blotting, immunohistochemistry, and RT-PCR were used to investigate the expression of BDH2 in GC specimens and cell lines. Its correlation with the clinicopathological characteristics and prognosis of GC patients was analysed. Functional assays, such as CCK-8 and TUNEL assays, transmission electron microscopy, and an in vivo tumour growth assay, were performed to examine the proliferation, apoptosis, and autophagy of GC cells. Related molecular mechanisms were clarified by luciferase reporter, coimmunoprecipitation, and ubiquitination assays.
Results
BDH2 was markedly downregulated in GC tissues and cells, and the low expression of BDH2 was associated with poor survival of GC patients. Functionally, BDH2 overexpression significantly induced apoptosis and autophagy in vitro and in vivo. Mechanistically, BDH2 promoted Keap1 interaction with Nrf2 to increase the ubiquitination level of Nrf2. Ubiquitination/degradation of Nrf2 inhibited the activity of ARE to increase accumulation of reactive oxygen species (ROS), thereby inhibiting the phosphorylation levels of Akt
Ser473
and mTOR
Ser2448
.
Conclusions
Our study indicates that BDH2 is an important tumour suppressor in GC. BDH2 regulates intracellular ROS levels to mediate the PI3K/Akt/mTOR pathway through Keap1/Nrf2/ARE signalling, thereby inhibiting the growth of GC.
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
Subject
/ BDH2
/ Biomarkers, Tumor - genetics
/ Biomarkers, Tumor - metabolism
/ Biomedical and Life Sciences
/ Cancer
/ Esters
/ Female
/ Gene Expression Regulation, Neoplastic
/ Humans
/ Hydroxybutyrate Dehydrogenase - genetics
/ Hydroxybutyrate Dehydrogenase - metabolism
/ Male
/ Mice
/ NF-E2-Related Factor 2 - genetics
/ NF-E2-Related Factor 2 - metabolism
/ Nrf2
/ Oncology
/ PI3K
/ Plasmids
/ Reactive Oxygen Species - metabolism
/ ROS
/ Stomach Neoplasms - genetics
/ Stomach Neoplasms - metabolism
/ Stomach Neoplasms - pathology
/ Tumors
