Contribution of Notch signaling activation to human glioblastoma multiforme

Kanamori, Masayuki; Kawaguchi, Tomohiro; Nigro, Janice; Feuerstein, Burt G.; Berger, Mitchel S.; Miele, Lucio; Pieper, Russell O.

doi:10.3171/jns.2007.106.3.417

Cited by 194 publications

(173 citation statements)

References 32 publications

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“…Notch-1 and its ligands, Delta-like 1 and jagged-1 are overexpressed in glioma cell lines and tissues, and inhibition of them results in an increase of cell death, a decrease of cell proliferation and invasion, and promotion of differentiation, together with upregulation of glial fibrillary acidic protein and downregulation of vimentin expression. 32,47 Notch signaling is also critical for maintaining stemness of brain tumor stem-like cells. Inhibition of Notch pathway exhausts CD133 þ stem-like tumor cells and suppresses sphere formation in vitro and tumor formation in vivo.…”

Section: Discussionmentioning

confidence: 99%

c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

Yoon

Kim

et al. 2012

Oncogene

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Uncovering the mechanisms that govern the maintenance of stem-like cancer cells is critical for developing therapeutic strategies for targeting these cells. Constitutive activation of c-Jun N-terminal kinase (JNK) has been reported in gliomas and correlates with histological grade. Here, we found that JNK signaling is crucial for the maintenance of 'stemness' in glioma cells. Sphere-cultured glioma cells showed more phosphorylation of JNK compared with serum-containing monolayer cultures. Importantly, blockade of JNK signaling with SP600125 or small interfering RNAs targeting JNK1 or JNK2 significantly reduced the CD133 þ /Nestin þ population and suppressed sphere formation, colony formation in soft agar, and expression of stem cell markers in sphere-cultured glioma cells. Intriguingly, sphere-cultured glioma cells exhibited enhanced expression of Notch-2, but not Notch-1, -3 or -4, and JNK inhibition almost completely abrogated this increase. Blocking the phosphoinoside 3-kinase (PI3K)/Akt pathway with LY294002 or si-Akt also suppressed the self-renewal of sphere-cultured glioma cells. PI3K, but not Akt, had a role as an upstream kinase in JNK1/2 activation. In addition, treatment with si-JNK greatly increased etoposideand ionizing radiation (IR)-induced cell death in glioma spheres. Consistent with glioma cell lines, glioma stem-like cells isolated from primary patient glioma cells also had a higher activity of JNK and Notch-2 expression. Importantly, inhibition of JNK2 led to a decrease of Notch-2 expression and suppressed the CD133 þ /Nestin þ cell population in patient-derived primary glioma cells. Finally, downregulation of JNK2 almost completely suppressed intracranial tumor formation by glioma cells in nude mice. Taken together, these data demonstrate that JNK signaling is crucial for the maintenance of self-renewal and tumorigenicity of glioma stem-like cells and drug/IR resistance, and can be considered a promising target for eliminating stem-like cancer cells in gliomas.

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Section: Discussionmentioning

confidence: 99%

c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

Yoon

Kim

et al. 2012

Oncogene

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“…Recently, they were widely used as a tool in anti-cancer studies. An increasing number of reports are revealing that GSIs offer a potential clinical application in cancer therapeutics, including treatment of glioblastomas [11][12][13][14][15][16] . A phase I trial of the γ-secretase inhibitor MK-0752 has been performed, and the results show that it is well-tolerated in children with recurrent CNS malignancies.…”

Section: Discussionmentioning

confidence: 99%

γ-Secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway

Wang

2014

Acta Pharmacol Sin

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Aim: -cyclohexyloxy]-benzoic acid (t-AUCB) is a soluble epoxide hydrolase inhibitor that suppresses glioblastoma cell growth in vitro. The aim of this study was to examine whether the γ-secretase inhibitor N- [N-(3,5-difluorophenacetyl)-lalanyl]-S-phenylglycine t-butyl ester (DAPT) could sensitize glioma cells to t-AUCB-induced apoptosis. Methods: Both U251 and U87 human glioblastoma cell lines were tested. Cell growth was assessed using the cell counting kit-8. Cell apoptosis was detected with caspase-3 activity assay kits and flow cytometry. The protein levels in the p38 MAPK/MAPKAPK2/Hsp27 pathway in the cells were analyzed using Western blots. Results: Pretreatment with DAPT (2 μmol/L) substantially potentiated the growth inhibition caused by t-AUCB (200 μmol/L) in U251 and U87 cells. Furthermore, pretreatment with DAPT markedly increased t-AUCB-induced apoptosis of U251 and U87 cells. T-AUCB alone did not significant affect caspase-3 activity in the cells, but t-AUCB plus DAPT pretreatment caused significant increase of caspase-3 activity. Furthermore, pretreatment with DAPT completely blocked t-AUCB-induced phosphorylation of p38 MAPK, MAPKAPK2 and Hsp27 in the cells. Conclusion: The γ-secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway, suggesting that the combination of t-AUCB and DAPT may be a potentially effective strategy for the treatment of glioblastoma.

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“…Notch signaling potently promotes the proliferation of normal neural stem cell (NSC) and is required for the maintenance of neural progenitors both in vitro and in vivo (Mizutani et al, 2007). Aberrant Notch signaling has been found in a number types of tumors including gliomas (Purow etal., 2005;Kanamori et al, 2007). The role of Notch signaling in brain tumor stem cells was initially identified in medulloblastomas.…”

Section: Notch Signalingmentioning

confidence: 99%

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

et al. 2010

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Glioblastomas (GBMs) are highly lethal primary brain tumors. Despite current therapeutic advances in other solid cancers, the treatment of these malignant gliomas remains essentially palliative. GBMs are extremely resistant to conventional radiation and chemotherapies. We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells (GSCs) promotes therapeutic resistance. We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth, which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs. Furthermore, stem cell-like cancer cells (cancer stem cells) have been shown to promote metastasis. Although GBMs rarely metastasize beyond the central nervous system, these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection, and GSCs display an aggressive invasive phenotype. These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment. Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells, but also display critical distinctions that provide important clues into useful therapeutic targets. In this review, we summarize the current understanding and advances in glioma stem cell research, and discuss potential targeting strategies for future development of anti-GSC therapies.

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Contribution of Notch signaling activation to human glioblastoma multiforme

Abstract: Notch activation contributes to Ras-induced transformation of glial cells and to glioma growth, survival, or both and as such may represent a new target for GBM therapy.

Cited by 194 publications

References 32 publications

c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

γ-Secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

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