Targeting the PI3K/AKT/mTOR Signaling Pathway in Medulloblastoma

Dimitrova, Valeriya; Arcaro, Alexandre

doi:10.2174/1566524015666150114115427

Cited by 58 publications

(71 citation statements)

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“…Notably, we also observed that down-regulation of SNHG16 could lead to the repression of anti-apoptotic Bcl-2 proteins and PI3K/Akt pathway. Therefore, targeting Bcl-2 proteins and/or PI3K/Akt pathway could be a promising strategy to fight against gliomas [17-19]. Our findings indicated that SNHG16 might be a potential therapeutic target in treatment of gliomas.…”

Section: Discussionmentioning

confidence: 86%

LncRNA SNHG16 Functions as an Oncogene by Sponging MiR-4518 and Up-Regulating PRMT5 Expression in Glioma

Cai

et al. 2018

Cell Physiol Biochem

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Background/Aims: Long noncoding RNAs (lncRNAs) have recently emerged as novel and potentially promising therapeutic targets in various cancers. However, the expression pattern and biological function of lncRNAs in glioma remain largely elusive. In the present study, we investigated the functional role of an lncRNA, small nucleolar RNA host gene 16 (SNHG16), in glioma. Methods: The expression levels of SNHG16 and miR-4518 were measured using qRT-PCR. The relationship between the levels of SNHG16 and clinicopathologic features were statically analyzed. The levels of proteins were detected using western blot. Bioinformatics analysis and luciferase reporter assays were applied to the analysis of the relationship between SNHG16, miR-4518 and PRMT5. Cell viability and apoptosis were measured using MTT and apoptosis ELISA assay, respectively. Results: SNHG16 was highly expressed in glioma tissues and cell lines, which was related to poorer clinicopathologic features and shorter survival time. Knockdown of SNHG16 inhibits the viability and induces apoptosis of glioma cells. Further investigation revealed that SNHG16 could up-regulate the expression of miR-4518 targeted gene PRMT5 via acting as an endogenous sponge of miR-4518. Moreover, SNHG16 also affects the expression of Bcl-2 family proteins and the activation of PI3K/Akt signaling pathway. Conclusion: Our study revealed a novel SNHG16-miR-4518-PRMT5 pathway regulatory axis in glioma pathogenesis. SNHG16 could be used as a potential therapeutic target in the treatment of glioma.

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Section: Discussionmentioning

confidence: 86%

LncRNA SNHG16 Functions as an Oncogene by Sponging MiR-4518 and Up-Regulating PRMT5 Expression in Glioma

Cai

et al. 2018

Cell Physiol Biochem

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“…It may occur in a context suggestive of a Li Fraumeni syndrome ( TP53 mutations) but no recurrent cancer gene mutations have been found [6, 7]. Nevertheless, many of the mutations described so far affect key intracellular signaling pathways such as sonic hedgehog, Wnt/β-catenin and Phosphoinositide-3-Kinase (PI3K/AKT/mTOR) pathways.…”

Section: Introductionmentioning

confidence: 99%

BKM120 induces apoptosis and inhibits tumor growth in medulloblastoma

et al. 2017

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Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for nearly 20 percent of all childhood brain tumors. New treatment strategies are needed to improve patient survival outcomes and to reduce adverse effects of current therapy. The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) intracellular signaling pathway plays a key role in cellular metabolism, proliferation, survival and angiogenesis, and is often constitutively activated in human cancers, providing unique opportunities for anticancer therapeutic intervention. The aim of this study was to evaluate the pre-clinical activity of BKM120, a selective pan-class I PI3K inhibitor, on MB cell lines and primary samples. IC50 values of BKM120 in the twelve MB cell lines tested ranged from 0.279 to 4.38 μM as determined by cell viability assay. IncuCyte ZOOM Live-Cell Imaging system was used for kinetic monitoring of cytotoxicity of BKM120 and apoptosis in MB cells. BKM120 exhibited cytotoxicity in MB cells in a dose and time-dependent manner by inhibiting activation of downstream signaling molecules AKT and mTOR, and activating caspase-mediated apoptotic pathways. Furthermore, BKM120 decreased cellular glycolytic metabolic activity in MB cell lines in a dose-dependent manner demonstrated by ATP level per cell. In MB xenograft mouse study, DAOY cells were implanted in the flank of nude mice and treated with vehicle, BKM120 at 30 mg/kg and 60 mg/kg via oral gavage daily. BKM120 significantly suppressed tumor growth and prolonged mouse survival. These findings help to establish a basis for clinical trials of BKM120, which could be a novel therapy for the treatment of medulloblastoma patients.

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“…[13][14][15] Components of the PAM pathway are therefore being considered as potential drug targets [ Table 1] to inhibit the often fatal events of metastasis and cell invasion. [16][17][18] …”

Section: Introductionmentioning

confidence: 99%

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

Crespo¹,

Kind²,

Arcaro³

2016

JCMT

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The PI3K/AKT/mTOR (PAM) pathway is involved in a variety of cellular functions and often contributes to oncogenesis and cancer progression. It has been recognized that this pathway is frequently activated in the most common central nervous system cancers of adults and children, malignant gliomas and medulloblastomas (MB). In these tumors, the PAM network controls key functions necessary for cell invasion and metastasis, such as cell motility. This review summarizes the current knowledge about the role of PAM signaling in cell invasion and metastasis in gliomas and MB. Current approaches to inhibit cell invasion and metastasis by targeting the PAM pathway will also be discussed.

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Targeting the PI3K/AKT/mTOR Signaling Pathway in Medulloblastoma

Cited by 58 publications

References 0 publications

LncRNA SNHG16 Functions as an Oncogene by Sponging MiR-4518 and Up-Regulating PRMT5 Expression in Glioma

LncRNA SNHG16 Functions as an Oncogene by Sponging MiR-4518 and Up-Regulating PRMT5 Expression in Glioma

BKM120 induces apoptosis and inhibits tumor growth in medulloblastoma

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

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