PIK3CA regulates development of diabetes retinopathy through the PI3K/Akt/mTOR pathway.
Ontology highlight
ABSTRACT:
SUBMITTER: Guan R
PROVIDER: S-EPMC10775978 | biostudies-literature | 2024
REPOSITORIES: biostudies-literature
Publications
PIK3CA regulates development of diabetes retinopathy through the PI3K/Akt/mTOR pathway.
Guan Ruijuan R Kang Zefeng Z Li Ling L Yan Xin X Gao Tianpeng T
PloS one 20240109 1
<h4>Objective</h4>To explore their association with the development of diabetes retinopathy (DR), single nucleotide polymorphism (SNP) mutations were screened out by high-throughput sequencing and validated in patients diagnosed with DR. To understand the role of PIK3CA in the pathogenesis of DR and explore the relationship between PIK3CA,phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR),and DR, the effect of PIK3CA.rs17849079 mutation was investiga ...[more]
Similar Datasets
Project description:BackgroundCLOVES syndrome (OMIM# 612918) is a rare overgrowth disorder resulted from mosaic gain-of-function mutations in the PIK3CA gene. All the reported CLOVES-associated PIK3CA mutations are missense mutations affecting certain residues. We aim to investigate underlying mutation and its pathogenicity in a patient with CLOVES syndrome and to evaluate the inhibitory effects of the PI3K/AKT/mTOR pathway inhibitors.ResultsWe performed whole-exome sequencing (WES) and Sanger sequencing to detect underlying somatic mutations in the skin lesion of the patient. Quantitative real-time PCR (qRT-PCR) was employed to evaluate the mRNA abundance of PIK3CA in the patient's skin lesion. AKT phosphorylation level assessed by immunoblotting of lysates from transiently transfected cells was performed to evaluate the PIK3CA mutations and inhibitory effects of PI3K/AKT/mTOR pathway inhibitors. A somatic frameshift mutation c.3206_3207insG (p.X1069Trpfs*4) in PIK3CA was identified in the genomic DNA extracted from the vascular malformation sample of the patient. This mutation affects the canonical stop codon of PIK3CA (NM_006218.4) and is predicted to produce a prolonged protein with four additional residues. qRT-PCR demonstrated that the mRNA expression levels of the patient's affected skin tissue were comparable compared to the normal control. In vitro studies revealed that p.X1069Trpfs*4 mutant exhibited increased AKT phosphorylation significantly to that of the wildtype, which could be inhibited by PI3K/AKT/mTOR pathway inhibitors.ConclusionsWe have identified the first frameshift mutation in PIK3CA that causes CLOVES syndrome, which was confirmed to overactive PI3K/AKT/mTOR pathway by transient transfection assays. We also provided more evidence of ARQ092 to be a potential therapeutic option for PROS in vitro.
| S-EPMC8170820 | biostudies-literature
Project description:This study investigates the expression and functional roles of SUGT1 in ovarian cancer, utilizing data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects. Our analyses reveal that SUGT1 is significantly upregulated in ovarian cancer tissues compared to normal controls. We further explore the prognostic value of SUGT1, where elevated expression correlates with poorer patient outcomes, particularly in ovarian cancer. The functional implications of SUGT1 in cancer biology were assessed through in vitro and in vivo experiments. Gene Set Enrichment Analysis (GSEA) indicates a significant association between high SUGT1 expression and the activation of glycolytic pathways, suggesting a potential role in metabolic reprogramming. Inhibition of SUGT1 via siRNA in ovarian cancer cell lines results in decreased proliferation and increased apoptosis, along with reduced migration and invasion capabilities. Additionally, our study identifies the transcription factor ELF1 as a significant regulator of SUGT1 expression. Through promoter analysis and chromatin immunoprecipitation, we demonstrate that ELF1 directly binds to the SUGT1 promoter, enhancing its transcription. This regulatory mechanism underscores the importance of transcriptional control in cancer metabolism, providing insights into potential therapeutic targets. Our findings establish SUGT1 as a crucial player in the oncogenic processes of ovarian cancer, influencing both metabolic pathways and transcriptional regulation. This highlights its potential as a biomarker and therapeutic target in managing ovarian cancer.
| S-EPMC11379980 | biostudies-literature
Project description:PurposeTransthyretin (TTR) plays a regulatory role in a variety of diabetes-related diseases. The objective of this work was to probe whether TTR affects diabetic retinopathy (DR) through the VEGFA/PI3K/AKT pathway.MethodsHigh glucose (HG, 25 mM) was used to treat human retinal microvascular endothelial cells (hRMECs) and C57BL/6J mice were intraperitoneally injected with STZ (50 mg/kg) to construct a DR model. In vitro, the effect of TTR on DR was evaluated by measuring hRMEC proliferation, migration, and angiogenesis. The changes in retinal tissue were observed by hematoxylin and eosin staining in vivo. ELISA, immunohistochemistry, and immunofluorescence staining were used to measure VEGFA or CD31 levels. The levels of all proteins were evaluated through Western blot.ResultsThe increase of proliferation, migration, and angiogenesis and decrease of apoptosis in hRMECs caused by HG were notably reversed by TTR. TTR greatly impeded HG-raised VEGFA, PI3K p-p85, and p-AKT in hRMECs. Inhibition of TTR further exacerbated the effect of HG-induced hRMECs. Inhibition of VEGFA reversed the effect of HG-induced hRMECs. VEGFA neutralized the function of TTR on cell proliferation, apoptosis, migration, and angiogenesis in HG-triggered hRMECs. It was further confirmed in vivo that TTR can alleviate the occurrence of DR in diabetic mice models.ConclusionsTTR significantly restrained the progression of DR via molecular modulation of the VEGFA/PI3K/AKT axis.
| S-EPMC10833055 | biostudies-literature
Project description:Colon adenocarcinoma (COAD) is the most common type of gastrointestinal cancer and is still the third leading cause of cancer-related mortality worldwide. Therefore, finding new and promising drugs to eradicate cancer may be a feasible method to treat COAD patients. Cys2-His2 zinc finger proteins (ZFPs) is one of the largest transcription factor family and many of them are highly involved in regulation of cell differentiation, proliferation, apoptosis, and neoplastic transformation. In this study, we identified a tumor-inhibiting factor, ZNF549, which expressed lowly in COAD tissues and COAD cell lines (HT29, HCT116, SW480, LoVo, and SW620). Overexpression of ZNF549 inhibit the ability of COAD cell proliferation and migration. On the contrary, decreasing the ZNF549 expression level promote the ability of COAD cell proliferation and migration. Through bioinformatics analysis, we found that ZNF549 was a potential target of hsa-miR-708-5p (miR-708-5p). Furthermore, we verified the possibility of miR-708-5p targeting the ZNF549 gene, and miR-708-5p inhibited the expression of ZNF549 by luciferase reporter assays, qRT-PCR and western blot assays. Moreover, the relationship between miR-708-5p and phosphatidylinositol 3-kinase/AKt (PI3K/AKt) signal pathway was elucidated. Overexpression and inhibition of miR-708-5p resulted in increased and decreased expression of p-AKt and p-PI3K in HCT116 cells, respectively. RT-qPCR and western blot assays results demonstrated that miR-708-5p regulated COAD cells development by promoting the process of Epithelial-mesenchymal transition (EMT) through PI3K/AKt signaling pathway. In summary, our findings demonstrated that ZNF549, the target gene of miR-708-5p, functions as a tumor suppressor to inhibit COAD cell lines proliferation and migration through regulate the PI3K/AKt signal pathway.
| S-EPMC7541523 | biostudies-literature
Project description:While hundreds of cancer-associated long noncoding RNAs (lncRNAs) have been discovered, their functional role in cancer cells is still largely a mystery. An increasing number of lncRNAs are recognized to function in the cytoplasm, e.g., as modulators of translation. Here, we investigated the detailed molecular identity and functional role of EPCART, a lncRNA we previously discovered to be a potential oncogene in prostate cancer (PCa). First, we interrogated the transcript structure of EPCART and then confirmed EPCART to be a non-peptide-coding lncRNA using in silico methods. Pathway analysis of differentially expressed protein-coding genes in EPCART knockout cells implied that EPCART modulates the translational machinery of PCa cells. EPCART was also largely located in the cytoplasm and at the sites of translation. With quantitative proteome analysis on EPCART knockout cells we discovered PDCD4, an inhibitor of protein translation, to be increased by EPCART reduction. Further studies indicated that the inhibitory effect of EPCART silencing on translation was mediated by reduced activation of AKT and inhibition of the mTORC1 pathway. Together, our findings identify EPCART as a translation-associated lncRNA that functions via modulation of the PI3K/AKT/mTORC1 pathway in PCa cells. Furthermore, we provide evidence for the prognostic potential of PDCD4 in PCa tumors in connection with EPCART.
| S-EPMC11489079 | biostudies-literature
Project description:BackgroundAngelica Sinensis (AS), a folk medicine, has long been used in ergogenic aids for athletes, but there is little scientific evidence supporting its effects. We investigated whether AS induces hypertrophy in myotubes through the phosphatidylinositol 3-kinase (PI3K)/Akt (also termed PKB)/mammalian target of the rapamycin (mTOR) pathway.MethodsAn in vitro experiment investigating the induction of hypertrophy in myotubes was conducted. To investigate whether AS promoted the hypertrophy of myotubes, an established in vitro model of myotube hypertrophy with and without AS was used and examined using microscopic images. The role of the PI3K/Akt/mTOR signaling pathway in AS-induced myotube hypertrophy was evaluated. Two inhibitors, wortmannin (an inhibitor of PI3K) and rapamycin (an inhibitor of mTOR), were used.ResultThe results revealed that the myotube diameters in the AS-treated group were significantly larger than those in the untreated control group (P?<?0.05). Wortmannin and rapamycin inhibited AS-induced hypertrophy. Furthermore, AS increased Akt and mTOR phosphorylation through the PI3K pathway and induced myotube hypertrophy.ConclusionThe results confirmed that AS induces hypertrophy in myotubes through the PI3K/Akt/mTOR pathway.
| S-EPMC4229743 | biostudies-literature
Project description:BackgroundActivating mutations in the pathway of phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) occur in 43-70% of breast cancer brain metastasis patients. To date, the treatment of these patients presents an ongoing challenge, mainly because of the lack of targeted agents that are able to sufficiently penetrate the blood-brain barrier. GDC-0068 is a pan-Akt inhibitor that has shown to be effective in various preclinical tumor models as well as in clinical trials. The purpose of this study was to analyze the efficacy of GDC-0068 in a breast cancer brain metastases model.MethodsIn in vitro studies, antitumor activity of GDC-0068 was assessed in breast cancer cells of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutant and PIK3CA-wildtype breast cancer cell lines using cell viability and apoptosis assays, cell cycle analysis, and western blots. In vivo, the efficacy of GDC-0068 was analyzed in a PIK3CA-mutant breast cancer brain metastasis orthotopic xenograft mouse model and evaluated by repeated bioluminescent imaging and immunohistochemistry.ResultsGDC-0068 decreased cell viability, induced apoptosis, and inhibited phosphorylation of proline rich Akt substrate 40 kDa and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines compared with PIK3CA-wildtype cell lines. In vivo, treatment with GDC-0068 notably inhibited the growth of PIK3CA-mutant tumors and resulted in a significant survival benefit compared with sham, whereas no effect was detected in a PIK3CA-wildtype model.ConclusionsThis study suggests that the Akt inhibitor GDC-0068 may be an encouraging targeted treatment strategy for breast cancer brain metastasis patients with activating mutations in the PI3K pathway. These data provide a rationale to further evaluate the efficacy of GDC-0068 in patients with brain metastases.
| S-EPMC6827829 | biostudies-literature
Project description:The present study examined the expression of mammalian target of rapamycin (mTOR) and mutations in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway in 54 patients with typical carcinoid tumours (TC) or atypical carcinoid tumours (AC). In total, 54 bronchopulmonary neuroendocrine tumour (NET) surgical specimens, consisting of 17 TC, 8 AC, 17 large-cell neuroendocrine carcinoma (LCNEC), and 12 small-cell lung carcinoma (SCLC) samples, were tested for mTOR by immunohistochemistry, and 104 exon sites were tested in the PI3K/AKT/mTOR pathway by nested polymerase chain reaction. It was found that the positive rates for mTOR expression in TC/AC and LCNEC/SCLC were 60 (15/25) and 55.2% (16/29), respectively. In total, 4 missense mutations were found in 3 patients with TC/AC, including mutations in exon 48 of mTOR (c.6667C>T), exon 21 of tuberous sclerosis complex (TSC) 1 (c.2765G>A), and exons 12 (c.1265C>T) and 19 (c.2148C>T) of TSC2. To the best of our knowledge, mutations in exon 48 of mTOR and exon 21 of TSC1 have not been previously reported. Tissues from patients with single mutations exhibited strong positive mTOR immunohistochemical staining, and tissues from patients with double mutations were weakly positive. The same mutations were not observed in SCLC or LCNEC. In conclusion, gene mutations were observed and an association between the gene mutations and mTOR expression were indicated in the PI3K/AKT/mTOR pathway in TC/AC tumours. Those mutations may be driver genes and treatment targets.
| S-EPMC5529984 | biostudies-other
Project description:Novel therapeutics such as inhibitors of PI3K/Akt/mTOR pathway presents a unique opportunity for the management of diabetic retinopathy (DR). Second generation mTOR inhibitors have the prospect to be efficacious in managing various stages of disease progression in DR. During early stages, the mTOR inhibitors suppress HIF-1?, VEGF, leakage, and breakdown of the blood-retinal barrier. These mTOR inhibitors impart a pronounced inhibitory effect on inflammation, an early component with diverse ramifications influencing the progression of DR. These inhibitors suppress IKK and NF-?B along with downstream inflammatory cytokines, chemokines, and adhesion molecules. In proliferative DR, mTOR inhibitors suppress several growth factors that play pivotal roles in the induction of pathological angiogenesis. Lead mTOR inhibitors in clinical trials for ocular indications present an attractive treatment option for chronic use in DR with favorable safety profile and sustained ocular pharmacokinetics following single dose. Thereby, reducing dosing frequency and risk associated with chronic drug administration.
| S-EPMC3205601 | biostudies-other
Project description:The present study examined the potential function and underlying mechanisms of microRNA-125a (miR-125a) in thyroiditis. Mice were subcutaneously administered with 100 µg porcine thyroglobulin weekly for 2 weeks to establish the thyroiditis model. Results of the in vivo study demonstrated that miR-125a serum expression was upregulated in thyroiditis mice compared with the control group. In vitro studies were performed on a mouse macrophage cell line in which a model of thyroiditis was established using 10 ng/ml human interferon-?. Upregulated miR-125a expression was achieved via mimic transfection. Increased miR-125a expression reduced autophagy and cell proliferation, increased the apoptotic rate and the expression of pro-inflammatory factors tumor necrosis factor-?, interleukin (IL)-1?, IL-6 and IL-18 via downregulation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. PI3K inhibition enhanced the ability of miR-125a to increase the inflammatory response in vitro via regulation of the PI3K/Akt/mTOR signaling pathway. These results suggest miR-125a inhibited autophagy in a model of thyroiditis through the PI3K/Akt/mTOR signaling pathway.
| S-EPMC6425124 | biostudies-literature