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

Acta Biochim Biophys Sin (Shanghai). 2022 Oct 25;54(11):1637-1647. doi: 10.3724/abbs.2022159.

Abstract

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 E17K 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 E17K 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.

Keywords: PI3K/AKT/mTOR; PTEN; miRNA.

MeSH terms

  • Animals
  • MTOR Inhibitors
  • Mice
  • MicroRNAs* / metabolism
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • MicroRNAs
  • MTOR Inhibitors
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • TOR Serine-Threonine Kinases
  • Pten protein, mouse

Grants and funding

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 81800550 and 81730078), the Haihe Laboratory of Cell Ecosystem Innovation Fund, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS) (No. 2021-1-I2 M-018), and the Chinese Foundation for Hepatitis Prevention and Control of the WBN Research Foundation (No. TQGB20190153).