The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression

Joy, Anna; Kapoor, Manisha; Georges, Joseph; Butler, Lacy; Chang, Yongchang; Li, Chaokun; Crouch, Acacia; Смирнов, Иван; Nakada, M.; Hepler, James; Marty, Max; Feuerstein, Burt G.

doi:10.1007/s11060-016-2220-z

Cited by 31 publications

(28 citation statements)

References 42 publications

(37 reference statements)

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“…However, interestingly, the role of AKT3 in tumor progression may be controversial. Recently a study indicated that AKT3 delayed tumor progression in glioblastoma, showing that a gene may play different roles in different cancers due to a distinct tumor microenvironment. Here, in mechanism dissection studies, we screened several genes that were associated with seminoma progression and the results showed that AKT3 was the most significantly changed molecule after TR4 manipulation, which promoted tumor progression through induction of EMT.…”

Section: Discussionmentioning

confidence: 99%

Testicular orphan receptor 4 promotes tumor progression and implies poor survival through AKT3 regulation in seminoma

Chen

Xia

et al. 2018

Cancer Science

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Seminoma is the most common testicular germ cell tumor worldwide and mainly occurs in 15‐35‐year‐old young men. Early studies have indicated that testicular nuclear receptor 4 (TR4) first cloned from testis is involved in the invasion and metastasis of several human tumors; however, little attention is paid to the function of TR4 in seminoma. Our immunohistochemical (IHC) staining results showed that patients with advanced stage tumors tended to have higher expression of TR4. Importantly, there was a significant association between elevated TR4 expression and reduced overall survival in seminoma patients. In vitro MTS, western blot and transwell assays, after manipulating TR4 expression in Tcam‐2 cells, revealed that TR4 induced epithelial‐to‐mesenchymal transition (EMT) and promoted Tcam‐2 cell proliferation and invasion. Mechanism dissection demonstrated that AKT3, a critical component in the signaling pathway, played a crucial role in mediating TR4‐promoted Tcam‐2 cell proliferation and invasion. We further revealed that TR4 modulated AKT3 at the transcriptional level via chromatin immunoprecipitation and luciferase assays. Meanwhile, addition of the AKT3 siRNA blocked the function of TR4. Overall, these findings first elucidate that TR4 is a novel prognostic marker and plays a critical role in the metastatic capacity of Tcam‐2 cells by EMT regulation and, consequently, targeting TR4‐AKT3 pathway may serve as a potential therapeutic approach for seminoma.

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Section: Discussionmentioning

confidence: 99%

Testicular orphan receptor 4 promotes tumor progression and implies poor survival through AKT3 regulation in seminoma

Chen

Xia

et al. 2018

Cancer Science

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“…6B). Recent studies have shown that Akt3 can significantly inhibit the glioma cell aggressiveness and slow down disease progression [75]. Akt3 is mainly expressed in the brain and is crucial for malignant glioma cell viability [76], which may be the key molecule in MMP13 regulation via IL13 [77].…”

Section: Discussionmentioning

confidence: 99%

MiRNAs Mediate GDNF-Induced Proliferation and Migration of Glioma Cells

Zhang

Dong²,

Guo

et al. 2017

Cell Physiol Biochem

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Background/Aims: Glial cell line-derived neurotrophic factor (GDNF) is an important factor promoting invasive glioma growth. This study was performed to reveal a unique mechanism of glioma cell proliferation and migration. Methods: Human U251 glioma cells were used to screen the optimal GDNF concentration and treatment time to stimulate proliferation and migration. MicroRNA (MiRNA) expression profiles were detected by microarray and confirmed by real-time polymerase chain reaction (PCR). The target genes of differentially expressed miRNAs were predicted by miRWalk, and those targeted by multiple miRNAs were screened with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. A regulatory miRNA network was constructed using ingenuity pathway analysis (IPA). Target gene expression of differentially expressed miRNAs was examined by real-time PCR or mRNA microarray. Results: The results show that 50 ng/mL GDNF for 24 h significantly promotes U251 glioma cell proliferation and migration (P < 0.05). Seven miRNAs (hsa-miR-194-5p, hsa-miR-152-3p, hsa-miR-205-5p, hsa-miR-629-5p, hsa-miR-3609, hsa-miR-183-5p, and hsa-miR-487b-3p) were significantly up-regulated after GDNF treatment (P < 0.05). These miRNAs are primarily involved in signal transduction, cell adhesion and cell cycle through mitogen-activated protein kinase (MAPK) signaling, focal adhesion and glioma signal pathways. Five of these miRNAs (hsa-miR-194-5p, hsa-miR-152-3p, hsa-miR-205-5p, hsa-miR-183-5p, and hsa-miR-487b-3p) co-regulate TP53 and Akt. mRNA expression levels of four genes co-targeted by two or more up-regulated miRNAs were significantly decreased after GDNF treatment (P < 0.05). Conclusion: GDNF treatment of U251 glioma cells significantly increased the expression of seven miRNAs involved in cell adhesion and the cell cycle.

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“…By the way, although AKT isoforms are observed to play different roles in GBM, including AKT3 delays tumor progression [27], as a matter of fact, the AKT inhibitor perifosine is tolerable but ineffective as monotherapy for GBM [28]. AKT inhibitors remain elusive and bear the weight of further examination in treating GBM.…”

Section: Profiling the Pi3k/akt Pathway In The Brain And Central Nervmentioning

confidence: 99%

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

et al. 2020

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Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial-mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/ AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.

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The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression

Cited by 31 publications

References 42 publications

Testicular orphan receptor 4 promotes tumor progression and implies poor survival through AKT3 regulation in seminoma

Testicular orphan receptor 4 promotes tumor progression and implies poor survival through AKT3 regulation in seminoma

MiRNAs Mediate GDNF-Induced Proliferation and Migration of Glioma Cells

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

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