Is phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway therapeutic target for esophageal adenocarcinoma.
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ABSTRACT:
SUBMITTER: Harada K
PROVIDER: S-EPMC6447035 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Non-small cell lung cancer (NSCLC) is a devastating disease with poor prognosis. Systemic chemotherapy has been the mainstay of treatment in advanced disease for many decades. Personalized targeted therapy such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) and crizotinib has significantly changed the treatment paradigm in NSCLC. The future success of development of molecular targeted therapy relies on the understanding of signal transduction pathways. The PI3K-Akt-mTOR pathway is commonly deregulated in human malignancy including NSCLC. Therefore, this pathway is a target for many therapeutic developments. This review will provide an overview of PI3K-Akt-mTOR signaling pathway, genetic alterations activating the pathway and clinical therapeutic development of pathway inhibitors.
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Project description:Radiotherapy is routinely used as a neoadjuvant, adjuvant or palliative treatment in various cancers. There is significant variation in clinical response to radiotherapy with or without traditional chemotherapy. Patients with a good response to radiotherapy demonstrate better clinical outcomes universally across different cancers. The PI3K/AKT/mTOR pathway upregulation has been linked to radiotherapy resistance. We reviewed the current literature exploring the role of inhibiting targets along this pathway, in enhancing radiotherapy response. We identified several studies using in vitro cancer cell lines, in vivo tumour xenografts and a few Phase I/II clinical trials. Most of the current evidence in this area comes from glioblastoma multiforme, non-small cell lung cancer, head and neck cancer, colorectal cancer, and prostate cancer. The biological basis for radiosensitivity following pathway inhibition was through inhibited DNA double strand break repair, inhibited cell proliferation, enhanced apoptosis and autophagy as well as tumour microenvironment changes. Dual PI3K/mTOR inhibition consistently demonstrated radiosensitisation of all types of cancer cells. Single pathway component inhibitors and other inhibitor combinations yielded variable outcomes especially within early clinical trials. There is ample evidence from preclinical studies to suggest that direct pharmacological inhibition of the PI3K/AKT/mTOR pathway components can radiosensitise different types of cancer cells. We recommend that future in vitro and in vivo research in this field should focus on dual PI3K/mTOR inhibitors. Early clinical trials are needed to assess the feasibility and efficacy of these dual inhibitors in combination with radiotherapy in brain, lung, head and neck, breast, prostate and rectal cancer patients.
| S-EPMC7281073 | biostudies-literature
Project description:High-frequency microsatellite-instable (MSI-H) tumors account for approximately 15% of colorectal cancers. Therapeutic decisions for colorectal cancer are empirically based and currently do not emphasize molecular subclassification despite an increasing collection of gene expression information. Our objective was to identify low molecular weight compounds with preferential activity against MSI colorectal cancers using combined gene expression data sets.Three expression/query signatures (discovery data set) characterizing MSI-H colorectal cancer were matched with information derived from changes induced in cell lines by 164 compounds using the systems biology tool "Connectivity Map." A series of sequential filtering and ranking algorithms were used to select the candidate compounds. Compounds were validated using two additional expression/query signatures (validation data set). Cytotoxic, cell cycle, and apoptosis effects of validated compounds were evaluated in a panel of cell lines.Fourteen of the 164 compounds were validated as targeting MSI-H cell lines using the bioinformatics approach; rapamycin, LY-294002, 17-(allylamino)-17-demethoxygeldanamycin, and trichostatin A were the most robust candidate compounds. In vitro results showed that MSI-H cell lines due to hypermethylation of MLH1 are preferentially targeted by rapamycin (18.3 versus 4.4 mumol/L; P = 0.0824) and LY-294002 (15.02 versus 10.37 mumol/L; P = 0.0385) when compared with microsatellite-stable cells. Preferential activity was also observed in MSH2 and MSH6 mutant cells.Our study shows that the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway is of special relevance in mismatch repair-deficient colorectal cancer. In addition, we show that amalgamation of gene expression information across studies provides a robust approach for selection of potential therapies corresponding to specific groups of patients.
| S-EPMC3425357 | biostudies-literature
Project description:BACKGROUND:With continuous advancement of industrial society, environmental pollution has become more and more serious. There has been an increase in infertility caused by environmental factors. Nonylphenol (NP) is a stable degradation product widely used in daily life and production and has been proven to affect male fertility. However, the underlying mechanisms therein are unclear. Thus, it is necessary to study the effect and mechanism of NP on spermatogonial stem cells (SSCs). AIM:To investigate the cytotoxic effect of NP on SSCs via the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. METHODS:SSCs were treated with NP at 0, 10, 20 or 30 µmol. MTT assay was performed to evaluate the effect of NP on the proliferation of SSCs. Flow cytometry was conducted to measure SSC apoptosis. The expression of Bad, Bcl-2, cytochrome-c, pro-Caspase 9, SOX-2, OCT-4, Nanog, Nanos3, Stra8, Scp3, GFR?1, CD90, VASA, Nanos2, KIT, PLZF and PI3K/AKT/mTOR-related proteins was observed by western blot, and the mRNA expression of SOX-2, OCT-4 and Nanog was detected by quantitative reverse transcription polymerase chain reaction. RESULTS:Compared with untreated cells (0 ?mol NP), SSCs treated with NP at all concentrations showed a decrease in cell proliferation and expression of Bcl-2, Nanog, OCT-4, SOX-2, Nanos3, Stra8, Scp3, GFR?1, CD90, VASA, Nanos2, KIT, and PLZF (P < 0.05), whereas the expression of Bad, cytochrome-c, and pro-Caspase 9 increased significantly (P < 0.05). We further examined the PI3K/AKT/mTOR pathway and found that the phosphorylation of PI3K, AKT, mTORC1, and S6K was significantly decreased by NP at all concentrations compared to that in untreated SSCs (P < 0.05). NP exerted the greatest effect at 30 ?mol among all NP concentrations. CONCLUSION:NP attenuated the proliferation, differentiation and stemness maintenance of SSCs while promoting apoptosis and oxidative stress. The associated mechanism may be related to the PI3K/AKT/mTOR pathway.
| S-EPMC7360990 | biostudies-literature
Project description:The phosphatidylinositol-3-kinase (PI3K)/Akt/target of rapamycin (TOR) signalling pathway controls cell growth and survival, and is targeted by a number of viruses at different phases of their infection cycle to control translation. Whether and how insect viruses interact with this pathway remain poorly addressed. Here, we investigated the role of PI3K/Akt/TOR signalling during lethal infection of insect cells with an insect parvovirus. Using Junonia coenia densovirus (JcDV; lepidopteran ambidensovirus 1) and susceptible insect cells as experimental models, we first described JcDV cytopathology, and showed that viral infection affects cell size, cell proliferation and survival. We deciphered the role of PI3K/Akt/TOR signalling in the course of infection and found that non-structural (NS) protein expression correlates with the inhibition of TOR and the shutdown of cellular synthesis, concomitant with the burst of viral protein expression. Together, these results suggest that NS proteins control the cellular translational machinery to favour the translation of viral mRNAs at the expense of cellular mRNAs. As a consequence of TOR inhibition, cell autophagy is activated. These results highlight new functions for NS proteins in the course of multiplication of an insect parvovirus.
| S-EPMC4772707 | biostudies-literature
Project description:The molecular mechanisms that determine the size and complexity of the neuronal dendritic tree are unclear. Here, we show that the phosphoinositide-3' kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway promotes the growth and branching of dendrites in cultured hippocampal neurons. Constitutively active mutants of Ras, PI3K, and Akt, or RNA interference (RNAi) knockdown of lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome Ten), induced growth and elaboration of dendrites that was blocked by mTOR inhibitor rapamycin and/or by overexpression of eIF-4E binding protein 1 (4E-BP1), which inhibits translation of 5' capped mRNAs. The effect of PI3K on dendrites was lost in more mature neurons (>14 d in vitro). Dendritic complexity was reduced by inhibition of PI3K and by RNAi knockdown of mTOR or p70 ribosomal S6 kinase (p70S6K, an effector of mTOR). A rapamycin-resistant mutant of mTOR "rescued" the morphogenetic effects of PI3K in the presence of rapamycin. By regulating global and/or local protein translation, and as a convergence point for multiple signaling pathways, mTOR could play a central role in the control of dendrite growth and branching during development and in response to activity.
| S-EPMC6725892 | biostudies-literature
Project description:BackgroundGastric cancer (GC) is one of the most common malignant tumors. Osteopontin (OPN) is thought to be closely related to the occurrence, metastasis and prognosis of many types of tumors.AimTo investigate the effects of OPN on the proliferation, invasion and migration of GC cells and its possible mechanism.MethodsThe mRNA and protein expression of OPN in the GC cells were analyzed by real-time quantitative-reverse transcription polymerase chain reaction and western blotting, and observe the effect of varying degree expression OPN on the proliferation and other behaviors of GC. Next, the effects of OPN knockdown on GC cells migration and invasion were examined. The short hairpin RNA (shRNA) and negative control shRNA targeting OPN-shRNA were transfected into the cells according to the manufacturer's instructions. Non transfected cells were classified as control in the identical transfecting process. 24 h after RNA transfection cell proliferation activity was detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide assay, and cell invasiveness and migration were detected by Trans well assay. Meanwhile, the expression of protein kinase B (AKT), matrix metalloproteinase 2 (MMP-2) and vascular endothelial growth factor (VEGF) in the human GC cell lines was detected by reverse transcription polymerase chain reaction and western blotting.ResultsThe results of this study revealed that OPN mRNA and protein expression levels were highly expressed in SGC-7901 cells. OPN knockdown by specific shRNA noticeably reduced the capabilities of proliferation, invasion and migration of SGC-7901 cells. Moreover, in the experiments of investigating the underlying mechanism, results showed that OPN knockdown could down-regulated the expression of MMP-2 and VEGF, it also decreased the phosphorylation of AKT. Meanwhile, the protein expression levels of MMP-2, VEGF and phosphorylated AKT was noticeable lower than that in control group in the GC cells after they were added to phosphatidylinositol-3-kinase (PI3K) inhibitor (LY294002).ConclusionThese results suggested that OPN though PI3K/AKT/mammalian target of rapamycin signal pathway to up-regulate MMP-2 and VEGF expression, which contribute SGC-7901 cells to proliferation, invasion and migration. Thus, our results demonstrate that OPN may serve as a novel prognostic biomarkers as well as a potential therapeutic targets for GC.
| S-EPMC10514723 | biostudies-literature
Project description:We investigated the genotype-dependent therapeutic potential of targeting the phosphoinositide 3-kinase (PI3K)/Akt pathway for thyroid cancer. Proliferation of TPC1, Hth7, FTC133, OCUT1, K1, and BCPAP cells that harbored PI3K/Akt-activating genetic alterations was potently inhibited by the Akt inhibitor perifosine, whereas SW1736, Hth74, WRO, KAT18, and TAD2 cells that harbored no genetic alterations had no or only modest responses. Inhibition of Akt phosphorylation by perifosine was seen in these cells. Genetic-dependent apoptosis was induced by perifosine in cells selectively tested. Similarly, potent inhibition of cell proliferation by the mammalian target of rapamycin (mTOR) inhibitor temsirolimus occurred in virtually all the cells harboring genetic alterations, whereas modest inhibition was seen in some of the cells not harboring genetic alterations. Temsirolimus inhibited the phosphorylation of p70S6K, a substrate of mTOR. Knockdown of Akt1/2 or mTOR by shRNA approach inhibited the proliferation and colony formation of FTC133 and OCUT1 cells that harbored genetic alterations in the PI3K/Akt pathway but had no effect on SW1736 and KAT18 cells that did not. Transfection with PIK3CA mutants greatly sensitized SW1736 cells to perifosine and temsirolimus. Growth of xenograft tumors derived from FTC133 cells but not SW1736 cells in nude mice was dramatically inhibited by perifosine. Thus, this work for the first time shows that genetic alterations in the PI3K/Akt pathway confer thyroid cancer cells addiction to this pathway and their sensitivity to inhibition by targeting Akt and mTOR. This genotype-based targeting of the PI3K/Akt pathway using Akt and mTOR inhibitors may offer an effective therapeutic strategy for thyroid cancer and warrants further studies.
| S-EPMC2756336 | biostudies-literature
Project description:The transcription factor SOX2 is essential for the maintenance of embryonic stem cells and normal development of the esophagus. Our previous study revealed that the SOX2 gene is an amplification target of 3q26.3 in esophageal squamous cell carcinoma (ESCC), and that SOX2 promotes ESCC cell proliferation in vitro. In the present study, we aimed to identify the mechanisms by which SOX2 promotes proliferation of ESCC cells. Using a phosphoprotein array, we assayed multiple signaling pathways activated by SOX2 and determined that SOX2 activated the AKT/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. LY294002, an inhibitor of phosphatidylinositol 3-kinase, and rapamycin, an inhibitor of mTORC1, suppressed the ability of SOX2 to enhance proliferation of ESCC cells in vitro. Effects of SOX2 knockdown, including reduced levels of phosphorylated AKT and decreased ESCC cell proliferation, were reversed with constitutive activation of AKT with knockdown of phosphatase and tensin homolog. In mouse xenografts, SOX2 promoted in vivo tumor growth of ESCC, which was dependent on AKT/mTORC1 activation. LY294002 suppressed the ability of SOX2 to enhance tumor growth of ESCC by reducing cell proliferation, but not by enhancing apoptosis. Furthermore, tissue microarray analysis of 61 primary ESCC tumors showed a positive correlation between expression levels of SOX2 and phosphorylated AKT. Our findings suggest that SOX2 promotes in vivo tumor growth of ESCC through activation of the AKT/mTORC1 signaling pathway, which enhances cell proliferation.
| S-EPMC7657236 | biostudies-literature
Project description:Allosteric inhibitors of the kinase mammalian target of rapamycin (mTOR) have demonstrated significant clinical activity in patients with advanced renal cell carcinoma (RCC). Unfortunately, substantial clinical responses to these rapalogues are seen only in a subset of patients with advanced RCC. Preclinical studies have identified multiple theoretical shortcomings of the rapalogues, and numerous novel agents directed against the phosphatidylinositol 3-kinase/Akt/mTOR pathway, which address many of these shortcomings, are in active clinical development. In this review, we discuss the preclinical and clinical experience with the rapalogues in RCC, potential mechanisms of resistance to the rapalogues, and the progress in the clinical development of novel agents directed against the phosphatidylinositol 3-kinase/Akt/mTOR pathway.
| S-EPMC3934425 | biostudies-literature