Estradiol induces JNK-dependent apoptosis in glioblastoma cells

Altiok, Nedret; Ersöz, Melike; Koyutürk, Meral

doi:10.3892/ol.2011.385

Cited by 26 publications

(20 citation statements)

References 25 publications

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“…To achieve this, the effect of E2 on the viability of glioblastoma cells was initially assessed. A previous study had indicated that E2 activates the c-Jun N-terminal kinase/c-Jun signaling cascade and inhibits the growth of rat C6 glioblastoma and human T98G glioblastoma cells, with an half maximal inhibitory concentration of 3.5 µM (34). The results of the present study indicated that E2 treatment for 24 h reduced the viability of C6 and U87-MG cells to 71.33 and 59.28%, respectively.…”

Section: Discussionsupporting

confidence: 58%

Natural product‑derived icaritin exerts anti‑glioblastoma effects by positively modulating estrogen receptor β

Zhang

Liang

et al. 2020

Exp Ther Med

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Glioblastoma is the most common malignancy of the central nervous system, and patients typically have a poor prognosis. Previous studies indicate a gender bias in the development of glioblastoma; women are at a lower risk compared with men, suggesting that estrogen may confer protective effects. Icaritin, a prenylflavonoid derivative from a Chinese herb of the Epimedium genus, selectively regulates the estrogen receptor (ER) and possesses anti-cancer properties. The aim of the present study was to investigate the protective effects of icaritin on glioblastoma and its underlying mechanisms, with a particular focus on its association with the ER. The results demonstrated that icaritin inhibited the growth of C6 and U87-MG glioblastoma cells in a dose-and time-dependent manner. At a concentration of 12.5 µM, icaritin induced apoptosis, which was characterized by the increased expression of the cleaved forms of caspases 3, 7, 8 and 9 and poly (ADP-ribose) polymerase, downregulation of BCL2 apoptosis regulator and upregulation of BCL2-associated X, apoptosis regulator expression. Additionally, icaritin inhibited the migration of C6 and U87-MG cells. The protein expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 were also downregulated following icaritin treatment. Furthermore, icaritin treatment increased the expression of estrogen receptor (ER)β and the phosphatase and tensin (PTEN) homolog oncoprotein, thus reducing the expression of downstream targets of PTEN; protein kinase B (Akt) and phosphorylated Akt. Subsequent experiments demonstrated that icaritin cooperates with 17β-estradiol to inhibit the growth of glioblastoma cells, and the inhibition of ERβ with the ERβ-specific antagonist ICI 182,780, attenuated the anti-glioblastoma effects of icaritin. In conclusion, the results of the present study demonstrate that the anti-glioblastoma effects of icaritin may be mediated by its modulation of ERβ.

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Section: Discussionsupporting

confidence: 58%

Natural product‑derived icaritin exerts anti‑glioblastoma effects by positively modulating estrogen receptor β

Zhang

Liang

et al. 2020

Exp Ther Med

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“…Previous studies showed that high concentrations of estradiol, under low growth-stimulated conditions, inhibit cell proliferation and increase apoptosis in ER-positive breast cancer cells through the sustained activation of the JNK pathway [12,22]. ese findings emphasize the basis for the antitumor effects of high-dose estrogen therapy in postmenopausal women approximately 40 years ago [20].…”

Section: Discussionmentioning

confidence: 80%

Role of 17β-Estradiol on Cell Proliferation and Mitochondrial Fitness in Glioblastoma Cells

Castracani

Longhitano

Distefano

et al. 2020

Journal of Oncology

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Gliomas are the most common primary tumors of the central nervous system (CNS) in the adult. Previous data showed that estrogen affects cancer cells, but its effect is cell-type-dependent and controversial. The present study aimed to analyze the effects of estradiol (E2, 5 nM) in human glioblastoma multiforme U87-MG cells and how it may impact on cell proliferation and mitochondrial fitness. We monitored cell proliferation by xCELLigence technology and mitochondrial fitness by assessing the expression of genes involved in mitochondrial biogenesis (PGC1α, SIRT1, and TFAM), oxidative phosphorylation (ND4, Cytb, COX-II, COX IV, NDUFA6, and ATP synthase), and dynamics (OPA1, MNF2, MNF1, and FIS1). Finally, we evaluated Nrf2 nuclear translocation by immunocytochemical analysis. Our results showed that E2 resulted in a significant increase in cell proliferation, with a significant increase in the expression of genes involved in various mechanisms of mitochondrial fitness. Finally, E2 treatment resulted in a significant increase of Nrf2 nuclear translocation with a significant increase in the expression of one of its target genes (i.e., heme oxygenase-1). Our results suggest that E2 promotes proliferation in glioblastoma cells and regulate the expression of genes involved in mitochondrial fitness and chemoresistance pathway.

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“…The top-ranked drugs from our approach include targeted cancer therapy, such as tamoxifen, cytotoxic cancer therapy, such as etoposide, and non-cancer drugs with supporting evidence from previous studies. For example, among the top ten predicted drugs, estradiol is a form of estrogen and induces JNK-dependent apoptosis in human GBM and rat glioma cells [5]; arsenic trioxide has demonstrated preclinical evidence in treating infiltrating astrocytomas [9]; and imipramine, an antidepressant and nerve pain medication, targets on the autophagic regulatory circuitry in gliomas and increased autophagy in tumor-bearing animals [28]. …”

Section: Resultsmentioning

confidence: 99%

Drug repurposing for glioblastoma based on molecular subtypes

Chen

2016

Journal of Biomedical Informatics

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A recent multi-platform analysis by The Cancer Genome Atlas identified four distinct molecular subtypes for glioblastoma (GBM) and demonstrated that the subtypes correlate with clinical phenotypes and treatment responses. In this study, we developed a computational drug repurposing approach to predict GBM drugs based on the molecular subtypes. Our approach leverages the genomic signature for each GBM subtype, and integrates the human cancer genomics with mouse phenotype data to identify the opportunity of reusing the FDA-approved agents to treat specific GBM subtypes. Specifically, we first constructed the phenotype profile for each GBM subtype using their genomic signatures. For each approved drug, we also constructed a phenotype profile using the drug target genes. Then we developed an algorithm to match and prioritize drugs based on their phenotypic similarities to the GBM subtypes. Our approach is highly generalizable for other disorders if provided with a list of disorder-specific genes. We first evaluated the approach in predicting drugs for the whole GBM. For a combined set of approved, potential and off-label GBM drugs, we achieved a median rank of 9.3%, which is significantly higher (p < e−7) than 45.7% for a recent approach that also uses the mouse phenotype data. Then we applied the approach on GBM subtypes. Analysis result shows the variations of enriched pathways, associated phenotypes and prioritized drugs across different subtypes. We ranked the first-line chemotherapy for GBM in different positions for each subtypes, and the rank variation was consistent with the previous finding on different drug responses among subtypes. In summary, this study makes an effort towards translating the molecular stratification into better survival for GBM.

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Estradiol induces JNK-dependent apoptosis in glioblastoma cells

Cited by 26 publications

References 25 publications

Natural product‑derived icaritin exerts anti‑glioblastoma effects by positively modulating estrogen receptor β

Natural product‑derived icaritin exerts anti‑glioblastoma effects by positively modulating estrogen receptor β

Role of 17β-Estradiol on Cell Proliferation and Mitochondrial Fitness in Glioblastoma Cells

Drug repurposing for glioblastoma based on molecular subtypes

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