Inhibition of the AKT/mTOR pathway negatively regulates PTEN expression via miRNAs

PI3K/AKT/mTOR pathway plays important roles in cancer development, and the negative role of PTEN in the PI3K/AKT/mTOR pathway is well known, but whether PTEN can be inversely regulated by PI3K/AKT/mTOR has rarely been reported. Here we aim to investigate the potential regulatory relationship between...

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Published in:Acta biochimica et biophysica Sinica 2022-11, Vol.54 (11), p.1637-1647
Main Authors: Wan, Linyan, Wang, Yanan, Li, Jie, Wang, Yani, Zhang, Hongbing
Format: Article
Language:English
Subjects:
Animals
Mice
MicroRNAs - metabolism
miRNA
MTOR Inhibitors
Phosphatidylinositol 3-Kinases - metabolism
PI3K/AKT/mTOR
Proto-Oncogene Proteins c-akt - metabolism
PTEN
PTEN Phosphohydrolase - genetics
PTEN Phosphohydrolase - metabolism
Signal Transduction
TOR Serine-Threonine Kinases - metabolism
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Summary:PI3K/AKT/mTOR pathway plays important roles in cancer development, and the negative role of PTEN in the PI3K/AKT/mTOR pathway is well known, but whether PTEN can be inversely regulated by PI3K/AKT/mTOR has rarely been reported. Here we aim to investigate the potential regulatory relationship between PTEN and Akt/mTOR inhibition in MEFs. AKT1 and TSC2 MEFs were treated with the AKT inhibitor MK2206 and the mTOR inhibitors rapamycin and Torin2. Our results reveal that inhibition of AKT or mTOR suppresses PTEN expression in AKT1 and TSC2 MEFs, but the transcription, subcellular localization, eIF4E-dependent translational initiation or lysosome- and proteasome-mediated degradation of PTEN change little, as shown by the real time PCR, nucleus cytoplasm separation assay and immunofluorescence analysis. Moreover, mTOR suppression leads to augmentation of mouse PTEN-3'UTR-binding miRNAs, including miR-23a-3p, miR-23b-3p, miR-25-3p and miR-26a-5p, as shown by the dual luciferase reporter assay and miRNA array analysis, and miRNA inhibitors collaborately rescue the decline of PTEN level. Collectively, our findings confirm that inhibition of mTOR suppresses PTEN expression by upregulating miRNAs, provide a novel explanation for the limited efficacy of mTOR inhibitors in the treatment of mTOR activation-related tumors, and indicate that dual inhibition of mTOR and miRNA is a promising therapeutic strategy to overcome the resistance of mTOR-related cancer treatment.
ISSN:1672-9145
1745-7270
DOI:10.3724/abbs.2022159