Role of the PI3K/AKT pathway and PTEN in otitis media.
Ontology highlight
ABSTRACT:
SUBMITTER: Lee HH
PROVIDER: S-EPMC7824983 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
Publications
Role of the PI3K/AKT pathway and PTEN in otitis media.
Lee Hwan Ho HH Chin Anthony A Pak Kwang K Wasserman Stephen I SI Kurabi Arwa A Ryan Allen F AF
Experimental cell research 20191213 1
Mucosal hyperplasia is common sequela of otitis media (OM), leading to the secretion of mucus and the recruitment of leukocytes. However, the pathogenic mechanisms underlying hyperplasia are not well defined. Here, we investigated the role of the AKT pathway in the development of middle mucosal hyperplasia using in vitro mucosal explants cultures and an in vivo rat model. The Akt inhibitor MK2206 treatment inhibited the growth of middle ear mucosal explants in a dose-dependent manner. In vivo, M ...[more]
Similar Datasets
Project description:The mammalian signalling pathway involving class I PI3K (phosphoinositide 3-kinase), PTEN (phosphatidylinositol 3-phosphatase) and PKB (protein kinase B)/c-Akt has roles in multiple processes, including cell proliferation and apoptosis. To facilitate novel approaches for genetic, molecular and pharmacological analyses of these proteins, we have reconstituted this signalling pathway by heterologous expression in the unicellular eukaryote, Saccharomyces cerevisiae (yeast). High-level expression of the p110 catalytic subunit of mammalian PI3K dramatically inhibits yeast cell growth. This effect depends on PI3K kinase activity and is reversed partially by a PI3K inhibitor (LY294002) and reversed fully by co-expression of catalytically active PTEN (but not its purported yeast orthologue, Tep1). Growth arrest by PI3K correlates with loss of PIP2 (phosphatidylinositol 4,5-bisphosphate) and its conversion into PIP3 (phosphatidylinositol 3,4,5-trisphosphate). PIP2 depletion causes severe rearrangements of actin and septin architecture, defects in secretion and endocytosis, and activation of the mitogen-activated protein kinase, Slt2. In yeast producing PIP3, PKB/c-Akt localizes to the plasma membrane and its phosphorylation is enhanced. Phospho-specific antibodies show that both active and kinase-dead PKB/c-Akt are phosphorylated at Thr308 and Ser473. Thr308 phosphorylation, but not Ser473 phosphorylation, requires the yeast orthologues of mammalian PDK1 (3-phosphoinositide-dependent protein kinase-1): Pkh1 and Pkh2. Elimination of yeast Tor1 and Tor2 function, or of the related kinases (Tel1, Mec1 and Tra1), did not block Ser473 phosphorylation, implicating another kinase(s). Reconstruction of the PI3K/PTEN/Akt pathway in yeast permits incisive study of these enzymes and analysis of their functional interactions in a simplified context, establishes a new tool to screen for novel agonists and antagonists and provides a method to deplete PIP2 uniquely in the yeast cell.
| S-EPMC1198941 | biostudies-literature
Project description:The PI3K/Akt/PTEN axis is one of the most important signaling pathways in tumorigenesis. Recently, mutation of PIK3CA has been highlighted due to the similarities of mutational hotspots in both dogs and humans. PIK3CA H1047R (c.3140A > G) has been discovered as the most common mutational hot spot in canine mammary tumor in recent studies, while the feature of PIK3CA-mutated canine mammary tumor is obscure. A total of 83 mammary samples classified as normal (n = 13), adenoma (n = 25), low-grade carcinoma (n = 21), and high-grade carcinoma (n = 24) were included in this study. Genomic DNA from each sample was extracted, amplified by conventional PCR, and analyzed through Sanger sequencing. Analysis for the expression of PIK3CA, Akt, p-Akt, and PTEN was performed by immunohistochemistry, and of Akt2 by RNA in situ hybridization. PIK3CA H1047R mutation was detected in 14.3% (10/70) of tumor samples. Dysregulation of p-Akt, Akt2, and PTEN was observed in mammary tumor samples, but only PTEN dysregulation was associated with PIK3CA H1047R mutation. The present study showed that dysregulation of components in the PI3K/Akt/PTEN pathway is a feature of canine mammary tumors, but this dysregulation is not directly correlated to the PIK3CA H1047R mutation except for PTEN expression.
| S-EPMC8300234 | biostudies-literature
Project description:The PTEN/PI3K/Akt signaling pathway, a key player in mediating apoptosis, metabolism, cell proliferation, and cell growth, is frequently dysregulated in many cancers. However, the pathway's prognostic impact in epithelial ovarian cancer (EOC) is still inconsistent. We performed a meta-analysis based on individual study outcomes to more precisely evaluate its clinical significance in EOC patients. Methods. We searched all potentially relevant studies published between January 1, 1990, and March 1, 2013, that assessed the association between PTEN, PI3K, and Akt status and survival in EOC. Meta-analysis was performed using a fixed-effect or random-effects model as appropriate. We investigated the possibility of publication bias through a funnel plot and identified the heterogeneity by I(2) statistics. Results. Eleven eligible studies were analyzed for PTEN, 5 for PI3K, and 11 for pAkt. High PI3K and pAkt expression was associated with poor overall survival (OS; pooled adjusted hazard ratio [HR] = 1.44, 95% CI, 1.08-1.91 for PI3K; HR = 1.60, 95% CI, 1.26-2.04 for pAkt). In addition, both the meta-analyses of univariate and multivariate estimates showed that only high pAkt expression was significantly associated with poor progression-free survival (PFS; pooled unadjusted HR = 1.24, 95% CI, 1.10-1.39; pooled adjusted HR = 1.65, 95% CI, 1.07-2.55). Conclusion. Published studies suggest that high pAkt expression is significantly associated with poor OS and PFS in EOC patients, but currently available evidence is insufficient to recommend that PTEN, PI3K, or Akt be used as prognostic predictors in EOC in clinical practice.
| S-EPMC4012960 | biostudies-literature
Project description:Overexpression of c-Myc is associated with worse outcomes in endometrial cancer, indicating that c-Myc may be a promising target for endometrial cancer therapy. A novel small molecule, JQ1, has been shown to block BRD4 resulting in inhibition of c-Myc expression and tumor growth. Thus, we investigated whether JQ1 can inhibit endometrial cancer growth in cell culture and xenograft models. In PTEN-positive endometrial cancer cells, JQ1 significantly suppressed cell proliferation via induction of G1 phase arrest and apoptosis in a dose-dependent manner, accompanied by a sharp decline in cyclin D1 and CDK4 protein expression. However, PTEN-negative endometrial cancer cells exhibited intrinsic resistance to JQ1, despite significant c-Myc inhibition. Moreover, we found that PTEN and its downstream PI3K/AKT signaling targets were modulated by JQ1, as evidenced by microarray analysis. Silencing of PTEN in PTEN-positive endometrial cancer cells resulted in resistance to JQ1, while upregulation of PTEN in PTEN-negative endometrial cancer cells increased sensitivity to JQ1. In xenografts models of PTEN-positive and PTEN-knock-in endometrial cancer, JQ1 significantly upregulated the expression of PTEN, blocked the PI3K/AKT signaling pathway and suppressed tumor growth. These effects were attenuated in PTEN-negative and PTEN-knockdown xenograft models. Thus, JQ1 resistance appears to be highly associated with the status of PTEN expression in endometrial cancer. Our findings suggest that targeting BRD4 using JQ1 might serve as a novel therapeutic strategy in PTEN-positive endometrial cancers.
| S-EPMC5341839 | biostudies-literature
Project description:BackgroundLong non-coding RNA PTENP1, the pseudogene of PTEN tumor suppressor, has been reported to exert its tumor suppressive function via modulation of PTEN expression in many malignancies, including breast cancer (BC). However, whether the PTENP1/miR-20a/PTEN axis exists and how it functions in BC progression remains elusive.MethodsThe levels of PTENP1, PTEN and miR-20a were measured by qRT-PCR. Furthermore, the breast cancer cells proliferation was further measured by CCK8 assay, colony formation assays, EDU and Ki67 staining. The migratory and invasive ability was determined by transwell assay. Flow cytometry, JC-1 and TUNEL assays were conducted to show the occurrence of apoptosis. Xenograft model was used to show the tumorigenesis of breast cancer cells.ResultsWe analyzed PTENP1 and PTEN levels in clinical BC samples and cell lines, and found that PTENP1 and PTEN were confirmed and closely correlated with the malignancy of BC cell lines and poor clinical prognosis. Moreover, alteration of PTENP1 affects BC cell proliferation, invasion, tumorigenesis and chemoresistance to adriamycin (ADR). Bioinformatic analysis and dual-luciferase reporter gene assay predicted that PTENP1 was a direct target of miR-20a, which was clarified an alternative effect on BC aggressiveness phenotype. In addition, PTENP1 functioned as an endogenous sponge of miR-20a to regulate PTEN expression, which mediated BC cells proliferation, invasion and drug resistance via activation the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. PI3K inhibitor LY294002 or siAkt also prevented BC cells progression.ConclusionCollectively, these data indicated that PTENP1/miR-20a/PTEN axis involved in the malignant behaviors of BC cells, illuminating the possible mechanism mediated by PTEN via PI3K/Akt pathway. Targeting PTENP1/miR-20a/PTEN may provide a potential diagnosis and treatment strategy for BC.
| S-EPMC6567415 | biostudies-literature
Project description:Duchenne muscular dystrophy is the most common and severe form of muscular dystrophy, and although the genetic basis of this disease is well defined, the overall mechanisms that define its pathogenesis remain obscure. Alterations in individual signaling pathways have been described, but little information is available regarding their putative implications in Duchenne muscular dystrophy pathogenesis. Here, we studied the status of various major signaling pathways in the Golden Retriever muscular dystrophy dog that specifically reproduces the full spectrum of human pathology. Using antibody arrays, we found that Akt1, glycogen synthase kinase-3beta (GSK3beta), 70-kDa ribosomal protein S6 kinase (p70S6K), extracellular signal-regulated kinases 1/2, and p38delta and p38gamma kinases all exhibited decreased phosphorylation in muscle from a 4-month-old animal with Golden Retriever muscular dystrophy, revealing a deep alteration of the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase pathways. Immunohistochemistry analysis revealed the presence of muscle fibers exhibiting a cytosolic accumulation of Akt1, GSK3beta, and phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN), an enzyme counteracting PI3K-mediated Akt activation. Enzymatic assays established that these alterations in phosphorylation and expression levels were associated with decreased Akt and increased GSK3beta and PTEN activities. PTEN/GSK3beta-positive fibers were also observed in muscle sections from 3- and 36-month-old animals, indicating long-term PI3K/Akt pathway alteration. Collectively, our data suggest that increased PTEN expression and activity play a central role in PI3K/Akt/GSK3beta and p70S6K pathway modulation, which could exacerbate the consequences of dystrophin deficiency.
| S-EPMC2671376 | biostudies-other
Project description:To comprehensively analyze the PTEN-PI3K-AKT pathway in T-ALL, we examined diagnostic DNA samples from a series of children with T-ALL by array CGH and sequence analysis, and identified genetic lesions in PTEN, PI3K or AKT in 47.7 % (n = 21 of 44) of cases. Furthermore, we identified a striking clustering of PTEN mutations in exon 7 in primary T-ALL patient samples, all of which encode mutations predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed in three of the four patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, while no induction failures occurred in the 12 cases with PTEN exon 7 mutations (P = 0.007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings provide a firm rationale for the development of therapies targeting the PI3K-AKT pathway in T-ALL.
2009-12-01 | GSE14959 | GEO
Project description:The present study aimed to explore the role of the PTEN/Akt/mTOR signaling pathway in the neurite outgrowth and apoptosis of cortical neurons. Cortical neurons were seeded on or adjacent to chondroitin sulfate proteoglycans. The length, number and crossing behavior of the neurites were calculated. Immunohistochemical staining and TUNEL data were analyzed. Neurites treated with PTEN inhibitor exhibited significant enhancements in elongation, initiation and crossing abilities when they encountered chondroitin sulfate proteoglycans in vitro. These effects disappeared when the PTEN/Akt/mTOR signaling pathway was blocked. Neurons exhibited significant enhancements in survival ability following PTEN inhibition. The present study demonstrated that PTEN inhibition can promote axonal elongation and initiation in cerebral cortical neurons, as well as the ability to cross the chondroitin sulfate proteoglycan border. In addition, PTEN inhibition is useful for protecting the neuron from apoptosis. The PTEN/Akt/mTOR signaling pathway is an important signaling pathway.
| S-EPMC6797942 | biostudies-literature
Project description:Among all cancer types, lung cancer has already become the leading cause of cancer-related death around the world. The molecular mechanism understanding this development is still needed to be improved to treat lung cancer. Stathmin (STMN1) was initially identified as a cytoplasmic protein phosphorylated responding to cell signal and controlled cell physiological processes. The dysregulation of STMN1 is found in various kinds of tumors. However, the molecular mechanism of STMN1 regulating lung cancer is still unclear. Here, we found that STMN1 was overexpressed in lung cancer tissues and associated with worse survival rates of lung cancer patients. Inhibition of STMN1 suppressed lung cancer cell growth, migration and invasion, and promoted drug sensitivity. Moreover, PTEN loss promoted STMN1 expression via PI3K/AKT pathway. PTEN loss ameliorated the inhibition of cell growth, migration and invasion, and drug sensitivity induced by STMN1 knockdown in lung cancer. The high expression of STMN1 was negatively correlated with the low expression of PTEN in lung cancer specimens. Overall, our work demonstrated that PTEN regulated the oncogenic function of STMN1 in lung cancer.
| S-EPMC8275769 | biostudies-literature
Project description:Gliomas represent 70% of all central system nervous tumors and are classified according to the degree of malignancy as low- or high-grade. The permanent activation of the EGFR/PI3K/AKT pathway by various genetic or post-translational alterations of EGFR, PI3KCA, and PTEN has been associated with increased proliferation and resistance to apoptosis. The present study aimed to analyze the molecular/genetic changes in the EGFR/PI3K/AKT/PTEN pathway between low-grade and high-grade gliomas in a sample of Colombian patients. A total of 30 samples were tested for PI3K and PTEN mutations, EGFR, PI3K, and AKT gene amplification, AKT, PI3K, BAX, Bcl2 expression levels, and phosphorylation of AKT and PTEN, EGFR and/or PI3K gene amplification was found in 50% of low-grade and 45% of high-grade ones. AKT amplification was found in 25% of the low-grade and 13.6% of the high-grade. The expression of PI3K, AKT, Bcl2, and BAX was increased particularly to a high degree. AKT phosphorylation was found in 66% of low-grade and 31.8% of high-grade. Increased phosphorylation of PTEN was found in 77% low-grade and 66% high-grade. Our results indicate that alterations in the EGFR/PI3K/AKT/PTEN pathway could be important in the initiation and malignant progression of this type of tumor.
| S-EPMC8699139 | biostudies-literature