Dataset Information

ITPKA phosphorylates PYCR1 and promotes the progression of glioma.

ABSTRACT: Glioma is one of the prevalent malignancies, and identifying therapeutic targets for glioma is highly important. Findings of current study revealed that inositol-trisphosphate 3-kinase A (ITPKA) was found abnormally over expressed and thereby exhibited poor prognosis with glioma. Extensive academic research has meticulously elucidated ITPKA's pivotal role in enhancing glioma cell proliferation and invasion, highlighting its significance in oncogenic pathways and cellular dynamics specific to aggressive brain tumors. Inhibiting the ITPKA has wide scope to reduce the tumorigenicity in gliomas in vivo. We also noticed that ITPKA interacts with PYCR1 and phosphorylates serine 29 of PYCR1. Phosphorylation of serine 29 inhibits the E3 ligase Stub1-mediated ubiquitination of PYCR1, thereby stabilizing its protein level. Based on our findings, it was determined that the phosphorylation of serine 29 in PYCR1 by ITPKA enhances the stability of the phosphorylated PYCR1 protein. This, in turn, involved significantly in oncogenic function of ITPKA in glioblastoma. Consequently, ITPKA holds promise as a potential target in prospective glioma therapy.

SUBMITTER: Luo X

PROVIDER: S-EPMC11336625 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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ITPKA phosphorylates PYCR1 and promotes the progression of glioma.

Luo Xiangying X Chen Tao T Deng Junyi J Liu Ziyuan Z Bi Changlong C Lan Song S

Heliyon 20240730 15

Glioma is one of the prevalent malignancies, and identifying therapeutic targets for glioma is highly important. Findings of current study revealed that inositol-trisphosphate 3-kinase A (ITPKA) was found abnormally over expressed and thereby exhibited poor prognosis with glioma. Extensive academic research has meticulously elucidated ITPKA's pivotal role in enhancing glioma cell proliferation and invasion, highlighting its significance in oncogenic pathways and cellular dynamics specific to agg ...[more]

PMID: 39170313

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Project description:BackgroundLung cancer is a serious threat to human life. It is of great significance to elucidate the pathogenesis of lung cancer and search for new markers. This study evaluate the clinical value of pyrroline-5-carboxylate reductase 1 (PYCR1) and explore its role and mechanisms in the malignant progression of lung cancer.MethodsPYCR1 expression and its relationship with prognosis were analyzed using a bioinformatics database. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were utilized to examine the expression of PYCR1 in lung cancer tissues and peripheral blood. PYCR1-overexpressing lung cancer cells were constructed, then the cell proliferative, migration, and invasion ability was examined by the MTT and Transwell assays. siRNA against PRODH and STAT3 inhibitor sttatic was used to further elucidate the underlying mechanisms. Luciferase and CHIP assays were carried out for validate the how PYCR1 regulated PD-L1 expression via STAT3. Xenograft experiment was performed to determine the role of PYCR1 in vivo.ResultsDatabase analysis showed that PYCR1 expression was significantly increased in lung cancer tissues, and its high expression predicted poor prognosis. Lung cancer tissue and peripheral blood of patients showed obviously increased PYCR1 expression, and the sensitivity and specificity of serum PYCR1 in the diagnosis of lung cancer were 75.7% and 60%, respectively. PYCR1 overexpression enhanced the proliferative, migration, and invasion abilities of lung cancer cells. Both PRODH silence and stattic effectively attenuated the function of PYCR1. Animal experiment and IHC data indicated that PYCR1 could activated STAT3 phosphorylation and PD-L1, as well as suppressed T cell infiltration in lung cancer. Finally, we also validated that PYCR1 promoted PD-L1 transcription by elevating STAT3 binding to the gene promoter.ConclusionPYCR1 has certain value in the diagnosis and prognosis of lung cancer. Moreover, through regulating JAK-STAT3 signaling pathway, PYCR1 significantly participated in process of lung cancer progression via the metabolism link between proline and glutamine, indicating that PYCR1 might be also a novel therapeutic target.

Project description:TRAF3IP3 was reportedly associated with poor prognosis in patients with melanoma; however, its role in glioma is unknown. We aimed to demonstrate the relationship between TRAF3IP3 and glioma and to investigate the potential role of TRAF3IP3 in glioma. Datasets were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We used the Wilcoxon rank-sum test to compared TRAF3IP3 expression in normal and glioma tissues. Kaplan-Meier analysis was performed to evaluate the correlation between TRAF3IP3 and patient survival rate. Gene set enrichment analysis (GSEA) was used to annotate the biological function of TRAF3IP3 in glioma. We also examined the effects of TRAF3IP3 on glioma progression, including characteristics such as cell proliferation, migration, and invasion, using cell proliferation, wound healing, and Transwell assays, respectively, paired with in vitro glioma cell lines and in vivo mouse xenograft models to determine the molecular mechanisms underlying these effects. High TRAF3IP3 expression in glioma tissues was associated with patients with neoplasm cancer tissue source site, and poorer overall survival (OS) (p = 0.03), which was validated using TCGA. GSEA revealed the enrichment of neuroactive ligand-receptor interactions, the olfactory pathway, proteasome pathway, cytokine-cytokine receptor interactions, and calcium signaling pathway in the TRAF3IP3 high-expression phenotype. TRAF3IP3 knockdown markedly suppressed the proliferation, migration, and invasion abilities of U251 glioma cells, whereas TRAF3IP3 overexpression notably promoted the progression of U118 cell tumors. Mechanistic studies revealed that TRAF3IP3 upregulated p-ERK expression in glioma cells. Notably, the ERK signaling pathway inhibitor U0126 drastically attenuated the effects of TRAF3IP3 on p-ERK and markedly blocked its tumor-promoting activity. TRAF3IP3 overexpression also promoted in vivo tumor growth in a nude mouse xenograft model. Collectively, TRAF3IP3 stimulates glioma cell proliferation, migration, and invasion, at least partly by activating the ERK signaling pathway. We hypothesize that TRAF3IP3 may participate in glioma development via the ERK signaling pathway and that elevated TRAF3IP3 expression may serve as a potential biomarker for glioma prognosis.

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ITPKA phosphorylates PYCR1 and promotes the progression of glioma.

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ITPKA phosphorylates PYCR1 and promotes the progression of glioma.

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