The PI3K pathway impacts stem gene expression in a set of glioblastoma cell lines

Martínez, E.; Vazquez, Neftali; Lopez, Alma; Fanniel, Victor; Sánchez, Lilia; Marks, R. William; Hinojosa, Leetoria; Cuello, Victoria; Cuevas, Marisa; Rodriguez, Angelica; Tomson, Cerin; Salinas, Andrea; Abad, Mark S.; Holguin, Martin; Garza, Noel; Arenas, Abraham J.; Abraham, K. E.; Maldonado, Luis A.; Rojas, Vivian; Basdeo, Alex; Schuenzel, Erin; Persans, Michael W.; Innis-Whitehouse, Wendy; Keniry, Megan

doi:10.1007/s00432-020-03133-w

Cited by 15 publications

(26 citation statements)

References 55 publications

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“…The PI3K/Akt pathway, which is related to cell growth and apoptosis, phosphorylates the substrate FOXO transcription factor to inactivate it and thereby reducing the expression of OCT4, because FOXO can directly bind to the OCT4 promoter to regulate OCT4 transcription, which indicates that targeting FOXO factors can reduce the generation of CSCs and the use of PI3K inhibitors clinically has potential risks ( 107 - 109 ). Likewise, phosphorylated Akt can phosphorylate OCT4, which increases tumorigenicity and self-renewal ability of CSCs ( 110 ).…”

Section: Signaling Pathways Related To Oct4mentioning

confidence: 99%

The Role and Specific Mechanism of OCT4 in Cancer Stem Cells: A Review

Zhang

Han

Zhu

et al. 2020

IJSC

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Recently, evidences show that cancer stem cells (CSCs) are a type of cancer cell group with self-renewal and play a huge role in tumor recurrence, metastasis, and drug resistance. Finding new treatment directions and targets for cancer prognosis and reducing mortality has become a top priority. OCT4, as a transcription factor, participates in maintaining the stem characteristics of CSCs, but the mechanism of OCT4 is often overlooked. In this review, we try to illustrate the mechanism by which OCT4 plays a role in CSCs from the perspective of genetic modification of OCT4, non-coding RNA, complexes and signaling pathways associated with OCT4. Our ultimate goal is to provide new targets for cancer treatment to prolong the survival of cancer patients.

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Section: Signaling Pathways Related To Oct4mentioning

confidence: 99%

The Role and Specific Mechanism of OCT4 in Cancer Stem Cells: A Review

Zhang

Han

Zhu

et al. 2020

IJSC

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“…The evolutionarily conserved phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway controls major physiological processes such as survival, proliferation, apoptosis, metabolism, motility, and growth [ 1 , 16 , 17 ]. The PI3K/AKT/mTOR pathway is often impacted in GBM by mutations in EGFR , PTEN, PIK3CA, AKT ( PKB ), and PDGFRA to increase pathway output [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…Even though FOXO transcription factors are known to perform tumor suppression activities, recent studies identified their involvement in cancer-promoting activities. Inhibition of the PI3K/AKT/mTOR pathway can lead to increased expression of stem markers such as OCT4 and ALPP , in part by activation of FOXO transcription factors [ 17 ]. In addition, FOXO transcription factors can act as stress response factors.…”

Section: Introductionmentioning

confidence: 99%

“…For example, Heinzen et al found that NVP-BEZ235 reduced growth and glucose consumption in GBM cell lines [ 32 ]. We previously investigated NVP-BEZ235 in the context of basal breast cancer and GBM and found that 50 nM NVP-BEZ235 enabled stem gene expression such as OCT4 in these settings but was also associated with decreased cell growth and apoptosis induction [ 17 , 33 ]. To better understand the molecular underpinnings for these phenotypes, we performed RNA-seq analysis with U87MG cells treated with NVP-BEZ235.…”

Section: Introductionmentioning

confidence: 99%

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PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells

Udawant

Litif

Lopez

et al. 2021

Cells

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Glioblastoma (GBM) is the most lethal primary brain cancer that lacks effective molecular targeted therapies. The PI3K/AKT/mTOR pathway is activated in 90% of all Glioblastoma multiforme (GBM) tumors. To gain insight into the impact of the PI3K pathway on GBM metabolism, we treated U87MG GBM cells with NVP-BEZ235 (PI3K and mTOR a dual inhibitor) and identified differentially expressed genes with RNA-seq analysis. RNA-seq identified 7803 differentially regulated genes in response to NVP-BEZ235. Gene Set Enrichment Analysis (GSEA) identified two glycolysis-related gene sets that were significantly enriched (p < 0.05) in control samples compared to NVP-BEZ235-treated samples. We validated the inhibition of glycolytic genes by NVP-BEZ235 and examined the impact of the FOXO1 inhibitor (AS1842856) on these genes in a set of GBM cell lines. FOXO1 inhibition alone was associated with reduced LDHA expression, but not ENO1 or PKM2. Bioinformatics analyses revealed that PI3K-impacted glycolytic genes were over-expressed and co-expressed in GBM clinical samples. The elevated expression of PI3K-impacted glycolytic genes was associated with poor prognosis in GBM based on Kaplan–Meier survival analyses. Our results suggest novel insights into hallmark metabolic reprogramming associated with the PI3K-mTOR dual inhibition.

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“…A study used CRISPR-Cas9 knockout of FOXO3 (forkhead box O3) gene in U87MG cells, causing decreases in expression of the cancer stem cell markers Oct4 and Sox2 [ 101 ]. Another study has used CRISPR-Cas9 editing to delete FOXG1 (forkhead box G1) showing that deletion of FOXG1 in GBM cell line increases their differentiation to astrocytes [ 102 ].…”

Section: Crispr-cas9 Editing Of the Genes That Regulate Self-renewal Capacity In Gbmmentioning

confidence: 99%

Applications of CRISPR-Cas9 Technology to Genome Editing in Glioblastoma Multiforme

Al-Sammarraie

Ray

2021

Cells

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Glioblastoma multiforme (GBM) is an aggressive malignancy of the brain and spinal cord with a poor life expectancy. The low survivability of GBM patients can be attributed, in part, to its heterogeneity and the presence of multiple genetic alterations causing rapid tumor growth and resistance to conventional therapy. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) nuclease 9 (CRISPR-Cas9) system is a cost-effective and reliable gene editing technology, which is widely used in cancer research. It leads to novel discoveries of various oncogenes that regulate autophagy, angiogenesis, and invasion and play important role in pathogenesis of various malignancies, including GBM. In this review article, we first describe the principle and methods of delivery of CRISPR-Cas9 genome editing. Second, we summarize the current knowledge and major applications of CRISPR-Cas9 to identifying and modifying the genetic regulators of the hallmark of GBM. Lastly, we elucidate the major limitations of current CRISPR-Cas9 technology in the GBM field and the future perspectives. CRISPR-Cas9 genome editing aids in identifying novel coding and non-coding transcriptional regulators of the hallmarks of GBM particularly in vitro, while work using in vivo systems requires further investigation.

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The PI3K pathway impacts stem gene expression in a set of glioblastoma cell lines

Cited by 15 publications

References 55 publications

The Role and Specific Mechanism of OCT4 in Cancer Stem Cells: A Review

The Role and Specific Mechanism of OCT4 in Cancer Stem Cells: A Review

PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells

Applications of CRISPR-Cas9 Technology to Genome Editing in Glioblastoma Multiforme

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