Wnt/beta-catenin and PI3K/Akt/mTOR Signaling Pathways in Glioblastoma: Two Main Targets for Drug Design: A Review

Shahcheraghi, Seyed Hossein; Tchokonte-Nana, Venant; Lotfi, Marzieh; Lotfi, Malihe; Ghorbani, Ahmad; Sadeghnia, Hamid Reza

doi:10.2174/1381612826666200131100630

Cited by 92 publications

(61 citation statements)

References 73 publications

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“…The above results showed that PODNL1 could promote cell proliferation, migration and inhibit EMT in glioma cells. Currently, accumulating studies have reported that Akt/mTOR pathway directly regulates malignant behaviors in glioma [12,13]. Thus, we supposed that PODNL1 aggravated malignant behaviors through Akt/mTOR pathway in glioma cells.…”

Section: Podnl1 Promoted Cell Proliferation and Migration Via Akt/mtomentioning

confidence: 87%

PODNL1 promotes cell proliferation and migration in glioma via regulating Akt/mTOR pathway

Geng

Zuo

et al. 2020

J. Cancer

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Background and Aims: Emerging studies have determined that the small leucine-rich proteoglycan (SLRP) family can aggravate tumor progression. However, the biological function of podocan-like protein 1 (PODNL1), a novel member of the SLRP family, has not been investigated. Therefore, our study focused on the function and regulatory mechanism of PODNL1 in glioma. Methods: Both the Gene Expression Profiling Interactive Analysis (GEPIA) and the Chinese Glioma Genome Atlas (CGGA) database were used to analyze the expression level and survival risk of PODNL1 in glioma. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were applied to detect the mRNA and protein expression, respectively. Celltiter-Glo and colony formation assays were used to evaluate cell proliferation. Migration capacity was measured by Transwell and wound healing assays. Flow cytometry was utilized to assess the apoptotic rate. Results: The expression of PODNL1 predicted the poor prognosis in glioma patients. Silencing of PODNL1 inhibited cell proliferation, migration, and induced epithelial-like phenotype. In addition, knockdown of PODNL1 also induced cell apoptosis. Moreover, the cell growth and migration inhibited by PODNL1 knockdown could be partially rescued with Akt activator. Conversely, PODNL1 overexpression promoted cell growth and migration, which were suppressed by Akt inhibitor. Conclusions: PODNL1, a promising predictive indicator of poor prognosis, resulted in greater proliferation, migration and epithelial-mesenchymal transition (EMT) process. Moreover, PODNL1 promoted aggressive glioma behavior by activating Akt/mTOR pathway, providing a novel therapeutic target for glioma.

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Section: Podnl1 Promoted Cell Proliferation and Migration Via Akt/mtomentioning

confidence: 87%

PODNL1 promotes cell proliferation and migration in glioma via regulating Akt/mTOR pathway

Geng

Zuo

et al. 2020

J. Cancer

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“…Change in calcium signaling is a major modulator of the glial cell behavior [43]. -PI3K-Akt signaling (hereafter denoted by PA) is pivotal for the growth, metabolism, survival, angiogenesis, autophagy, and chemotherapy resistance of the malignant astrocytic glioma [44]. -Chemokine signaling (CS) between astrocytes and oligodendrocytes, most likely the main crosstalk in our experiment, is important for glial development and stimulating regeneration and repair [45].…”

Section: Pathway Analysismentioning

confidence: 93%

Cellular Environment Remodels the Genomic Fabrics of Functional Pathways in Astrocytes

Iacobaş

Stout

et al. 2020

Genes

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We profiled the transcriptomes of primary mouse cortical astrocytes cultured alone or co-cultured with immortalized precursor oligodendrocytes (Oli-neu cells). Filters between the cell types prevented formation of hetero-cellular gap junction channels but allowed for free exchange of the two culture media. We previously reported that major functional pathways in the Oli-neu cells are remodeled by the proximity of non-touching astrocytes and that astrocytes and oligodendrocytes form a panglial transcriptomic syncytium in the brain. Here, we present evidence that the astrocyte transcriptome likewise changes significantly in the proximity of non-touching Oli-neu cells. Our results indicate that the cellular environment strongly modulates the transcriptome of each cell type and that integration in a heterocellular tissue changes not only the expression profile but also the expression control and networking of the genes in each cell phenotype. The significant decrease of the overall transcription control suggests that in the co-culture astrocytes are closer to their normal conditions from the brain. The Oli-neu secretome regulates astrocyte genes known to modulate neuronal synaptic transmission and remodels calcium, chemokine, NOD-like receptor, PI3K-Akt, and thyroid hormone signaling, as well as actin-cytoskeleton, autophagy, cell cycle, and circadian rhythm pathways. Moreover, the co-culture significantly changes the gene hierarchy in the astrocytes.

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“…Furthermore, specific molecules within this signaling pathway have been untested at the epigenetic and transcriptional levels. A need for a better understanding of the function and mechanisms of PI3K-AKT-mTOR signal transduction may eventually provide advanced diagnostic and treatment options for primary brain neoplasms [ 9 , 18 ]. This study aims to understand the significance of the EGFR-PI3K-AKT-mTOR signaling pathway and reveal differences between AKT1 , AKT2 , AKT3 , CHUK , GSK3β , EGFR , PTEN , and PIK3AP1 roles within different grades and types of diffuse brain gliomas.…”

Section: Introductionmentioning

confidence: 99%

Integrative cBioPortal Analysis Revealed Molecular Mechanisms That Regulate EGFR-PI3K-AKT-mTOR Pathway in Diffuse Gliomas of the Brain

Brlek

Kafka

Bukovac

et al. 2021

Cancers

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Diffuse gliomas are a heterogeneous group of tumors with aggressive biological behavior and a lack of effective treatment methods. Despite new molecular findings, the differences between pathohistological types still require better understanding. In this in silico analysis, we investigated AKT1, AKT2, AKT3, CHUK, GSK3β, EGFR, PTEN, and PIK3AP1 as participants of EGFR-PI3K-AKT-mTOR signaling using data from the publicly available cBioPortal platform. Integrative large-scale analyses investigated changes in copy number aberrations (CNA), methylation, mRNA transcription and protein expression within 751 samples of diffuse astrocytomas, anaplastic astrocytomas and glioblastomas. The study showed a significant percentage of CNA in PTEN (76%), PIK3AP1 and CHUK (75% each), EGFR (74%), AKT2 (39%), AKT1 (32%), AKT3 (19%) and GSK3β (18%) in the total sample. Comprehensive statistical analyses show how genomics and epigenomics affect the expression of examined genes differently across various pathohistological types and grades, suggesting that genes AKT3, CHUK and PTEN behave like tumor suppressors, while AKT1, AKT2, EGFR, and PIK3AP1 show oncogenic behavior and are involved in enhanced activity of the EGFR-PI3K-AKT-mTOR signaling pathway. Our findings contribute to the knowledge of the molecular differences between pathohistological types and ultimately offer the possibility of new treatment targets and personalized therapies in patients with diffuse gliomas.

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Wnt/beta-catenin and PI3K/Akt/mTOR Signaling Pathways in Glioblastoma: Two Main Targets for Drug Design: A Review

Cited by 92 publications

References 73 publications

PODNL1 promotes cell proliferation and migration in glioma via regulating Akt/mTOR pathway

PODNL1 promotes cell proliferation and migration in glioma via regulating Akt/mTOR pathway

Cellular Environment Remodels the Genomic Fabrics of Functional Pathways in Astrocytes

Integrative cBioPortal Analysis Revealed Molecular Mechanisms That Regulate EGFR-PI3K-AKT-mTOR Pathway in Diffuse Gliomas of the Brain

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