PTEN modulates neurites outgrowth and neuron apoptosis involving the PI3K/Akt/mTOR signaling pathway

Liu, Shen; Jia, Jun; Zhou, Hengxing; Zhang, Chi; Liu, Lu; Li, Jun; Lu, Lu; Li, Xueying; Kang, Yi No; Lou, Yongfu; Cai, Zhiwei; Ren, Yiming; Kong, Xiaohong

doi:10.3892/mmr.2019.10670

Cited by 18 publications

(12 citation statements)

References 47 publications

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“…PTEN expression has been reported to be negatively regulated by Notch1/Hes1 signaling (31,32). PTEN downregulation is regarded as an important inducer of the activation of the AKT/mTOR signaling pathway, which plays an important role in regulating the proliferation of multiple types of tumor cell lines (33,34). In the present study, we found that DAPT elevated the expression of PTEN by inhibiting Notch1/Hes1 signaling, further suppressing the AKT/mTOR signaling pathway.…”

Section: Discussionsupporting

confidence: 58%

DAPT suppresses proliferation and migration of hepatocellular carcinoma by regulating the extracellular matrix and inhibiting the Hes1/PTEN/AKT/mTOR signaling pathway

Qiu

Lu³

et al. 2021

J Gastrointest Oncol

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Background:The aim of the present study was to investigate the antitumor properties of N-(N-[3,5difluorophenacetyl]-1-alanyl)-S-phenylglycine t-butyl ester (DAPT) against hepatocellular carcinoma (HCC), as well as the underlying mechanism. Methods: Immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay were used to determine the expression of Notch1 in HCC tissues. The expression of Notch1 in 3 HCC cell lines was evaluated by qRT-PCR and Western blot. The proliferation ability of cells was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. Flow cytometry and Transwell assay were used to check the apoptosis and migration of HepG2 cells, respectively. Western blot was used to determine the expression level of Notch1, Hes1, Phosphatase and tensin homolog (PTEN), protein kinase B1 (AKT1), phosphorylated AKT1, mammalian target of rapamycin (mTOR), phosphorylated mTOR, intracellular adhesion molecule-1, vascular cell adhesion protein 1, matrix metalloproteinase (MMP)-2, MMP-9, and focal adhesion kinase in cells and tumor tissues. A HepG2 xenograft experiment was conducted to evaluate the in vivo antitumor properties of DAPT. Results: Notch1 was found to be significantly upregulated in both HCC tissues and cell lines. DAPT significantly inhibited the proliferation and migration of HepG2 cells in a dose-dependent manner, accompanied by the suppression of Notch1/Hes1 signaling, inactivation of AKT/mTOR signaling, downregulation of MMPs, and decreased expression of adhesion molecules. The activation of Notch1/ Hes1 or AKT/mTOR signaling removed the inhibitory effect of DAPT on the proliferation and migration of HepG2 cells, as well as the inhibitory properties of DAPT on the expression of MMPs and adhesion molecules. The antitumor properties and regulatory effect of DAPT against the extracellular matrix (ECM) and Hes1/PTEN/AKT/mTOR signaling were verified by the HepG2 xenograft experiments. Conclusions: DAPT could suppress the proliferation and migration of HCC by regulating the ECM and inhibiting the Hes1/PTEN/AKT/mTOR signaling pathway.

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Section: Discussionsupporting

confidence: 58%

DAPT suppresses proliferation and migration of hepatocellular carcinoma by regulating the extracellular matrix and inhibiting the Hes1/PTEN/AKT/mTOR signaling pathway

Qiu

Lu³

et al. 2021

J Gastrointest Oncol

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“…Meanwhile, our study also revealed that KCNK15-AS1 increased PTEN expression to inhibit AKT pathway, a master intracellular pathway affecting multiple transcription factors and signaling molecules, such as mTOR [ 33 ]. As a negative modulator of AKT [ 34 ], PTEN is verified as a typical tumor suppressor in many cancers, including PC [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

ALKBH5-mediated m6A demethylation of KCNK15-AS1 inhibits pancreatic cancer progression via regulating KCNK15 and PTEN/AKT signaling

Yue

Cheng

et al. 2021

Cell Death Dis

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Long noncoding RNAs (lncRNAs) are regarded as crucial regulators in tumor progression. Potassium two pore domain channel subfamily K member 15 and WISP2 antisense RNA 1 (KCNK15-AS1) has been confirmed to inhibit the migration and invasion of pancreatic cancer (PC) cells. However, its downstream mechanism and effect on other cellular functions in PC remain unknown. This study probed the function and potential mechanism of KCNK15-AS1 in PC cell growth. RT-qPCR and western blot were employed to measure gene expression in PC cells. ISH was applied to analyze KCNK15-AS1 expression in PC tissues. Functional assays were utilized to evaluate PC cell proliferation, apoptosis, migration and EMT. Mechanical experiments were adopted to detect gene interaction in PC cells. The obtained data indicated that KCNK15-AS1 was down-regulated in PC cells and tissues. Overexpressing KCNK15-AS1 hindered cell proliferation, migration and EMT while facilitated cell apoptosis in PC. Mechanically, alkylation repair homolog protein 5 (ALKBH5) was verified to induce m6A demethylation of KCNK15-AS1 to mediate KCNK15-AS1 up-regulation. KCNK15-AS1 combined with KCNK15 5’UTR to inhibit KCNK15 translation. Moreover, KCNK15-AS1 recruited MDM2 proto-oncogene (MDM2) to promote RE1 silencing transcription factor (REST) ubiquitination, thus transcriptionally upregulating phosphatase and tensin homolog (PTEN) to inactivate AKT pathway. In conclusion, our study first confirmed that KCNK15-AS1 hinders PC cell growth by regulating KCNK15 and PTEN, suggesting KCNK15-AS1 as a potential biomarker of PC.

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“…The amounts of PTEN protein as determined by the ELISA assay, were not altered by the short-term treatments of the cells (not shown). PTEN is currently the only established phosphatase capable of hydrolysing Phosphatidyl-Inositol(3,4,5) triphosphate (PIP3) to Phosphatidyl-Inositol(4,5) triphosphate (PI4,5P2) [61][62][63][64][65] . However, to ensure the specificity of the PTEN activity kit used in this study, the PTEN antibody was used to immune-deplete a sample of cell lysate along with a control which was immunoprecipitated using an isotype antibody.…”

Section: Exposure Of Cells To Tf or Par2-ap Activates Pten And Reducementioning

confidence: 99%

Activation of PAR2 by tissue factor induces the release of the PTEN from MAGI proteins and regulates PTEN and Akt activities

Mohammad

Greenman

Maraveyas

et al. 2020

Sci Rep

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Tissue factor (TF) signalling has been associated with alterations in Akt activity influencing cellular survival and proliferation. TF is also shown to induce signalling through activation of the protease activated receptor (PAR)2. Seven cell lines were exposed to recombinant-TF (rec-TF), or activated using a PAR2-agonist peptide and the phosphorylation state of PTEN, and the activities of PTEN and Akt measured. Furthermore, by measuring the association of PTEN with MAGI proteins a mechanism for the induction of signalling by TF was proposed. Short term treatment of cells resulted in de-phosphorylation of PTEN, increased lipid-phosphatase activity and reduced Akt kinase activity in most of the cell lines examined. In contrast, continuous exposure to rec-TF up to 14 days, resulted in lower PTEN antigen levels, enhanced Akt activity and increased rate of cell proliferation. To explore the mechanism of activation of PTEN by TF, the association of "membrane-associated guanylate kinase-with inverted configuration" (MAGI)1–3 proteins with PTEN was assessed using the proximity ligation assay and by co-immunoprecipitation. The interaction of PTEN with all three MAGI proteins was transiently reduced following PAR2 activation and explains the changes in PTEN activity. Our data is first to show that PAR2 activation directly, or through exposure of cells to TF releases PTEN from MAGI proteins and is concurrent with increases in PTEN phosphatase activity. However, prolonged exposure to TF results in the reduction in PTEN antigen with concurrent increase in Akt activity which may explain the aberrant cell survival, proliferation and invasion associated with TF during chronic diseases.

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PTEN modulates neurites outgrowth and neuron apoptosis involving the PI3K/Akt/mTOR signaling pathway

Cited by 18 publications

References 47 publications

DAPT suppresses proliferation and migration of hepatocellular carcinoma by regulating the extracellular matrix and inhibiting the Hes1/PTEN/AKT/mTOR signaling pathway

DAPT suppresses proliferation and migration of hepatocellular carcinoma by regulating the extracellular matrix and inhibiting the Hes1/PTEN/AKT/mTOR signaling pathway

ALKBH5-mediated m6A demethylation of KCNK15-AS1 inhibits pancreatic cancer progression via regulating KCNK15 and PTEN/AKT signaling

Activation of PAR2 by tissue factor induces the release of the PTEN from MAGI proteins and regulates PTEN and Akt activities

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