Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1

Fassl, Anne; Tagscherer, Katrin E.; Díaz, Mauricio Berriel; Llaguno, Sheila Alcantara; Campos, Benito; Kopitz, Juergen; Herold‐Mende, Christel; Herzig, Stephan; Schmidt, Mirko H. H.; Parada, Luis F.; Wiestler, Otmar D.; Roth, Wilfried

doi:10.1038/onc.2011.615

Cited by 60 publications

(63 citation statements)

References 50 publications

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“…However, Notch1 inhibition in vivo results in mammary tumor regression and reduces mammary tumor sphere-forming activity in vitro (25). The inhibition of the Notch1 pathway has been shown to allow glioblastoma cells to overcome apoptosis resistance and become sensitized to apoptosis that is induced by ionizing radiation, the death ligand tumor necrosis factor-related apoptosis-inducing ligand or the Bcl-2/Bcl-XL inhibitor ABT-737 (26). In conclusion, Notch1 may be a novel target for gastric cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of Notch1 intracellular domain and p21 proteins, and their clinical significance in gastric cancer

Luo

Zhou

et al. 2013

Oncology Letters

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Changes in the expression of the Notch1 intracellular domain (NICD) and p21 proteins have been shown to be closely associated with the development and progression of a number of cancers. The present study aimed to investigate the expression levels of the two proteins in gastric carcinoma and precancerous lesions, and to determine the clinical significance of this. A total of 109 gastric cancer, 57 precancerous gastric lesion, 50 chronic superficial gastritis and 17 normal gastric mucosa patients were recruited for immunohistochemical staining of NICD and p21 protein expression. The protein expression levels in the gastric cancer patient samples were associated with the clinicopathological and survival data. NICD protein levels were upregulated gradually from normal gastric mucosae through chronic superficial gastritis and precancerous gastric lesions to gastric cancer tissues (P<0.01), whereas p21 protein levels were downregulated accordingly (P<0.01). Increased NICD and a loss of p21 expression were closely associated with tumor dedifferentiation, depth of tumor invasion, lymph node metastasis, surface morphology and Lauren classification in gastric cancer. Thus, NICD expression was inversely associated with p21 expression. In addition, the overall survival rate was greater in NICD− and P21+ patients than in NICD+ and P21− patients, respectively (P<0.05). The COX regression multivariate analysis revealed that NICD+, p21−, depth of tumor invasion and lymph node metastasis were all independent prognostic factors for patients with gastric cancer. NICD and p21 proteins are differentially expressed in gastric cancer and the aberrant expression of these proteins is associated with an advanced tumor stage, tumor metastasis and overall patient survival. Future studies are required to further evaluate the two proteins as novel prognostic markers for patients with gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Differential expression of Notch1 intracellular domain and p21 proteins, and their clinical significance in gastric cancer

Luo

Zhou

et al. 2013

Oncology Letters

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“…However, one caveat of ABT-263 and related molecules is that tumors with high protein expression levels of Mcl-1, another member of the bcl-2 family of proteins with antiapoptotic properties, exhibit marked resistance against them. Glioblastomas display high levels of Mcl-1 expression, which is driven by several upstream cascades, such as NOTCH (11) or CREB3L2-ATF5 (12) signaling pathways. To overcome this resistance, several strategies have been devised, such as the targeting of a second molecular pathway that allows the depletion of high levels of endogenous Mcl-1 in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

PI3K and Bcl-2 Inhibition Primes Glioblastoma Cells to Apoptosis through Downregulation of Mcl-1 and Phospho-BAD

Pareja

MacLeod

Shu

et al. 2014

Molecular Cancer Research

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Glioblastoma multiforme (GBM) is a highly malignant human brain neoplasm with limited therapeutic options. GBMs display a deregulated apoptotic pathway with high levels of the antiapoptotic Bcl-2 family of proteins and overt activity of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Therefore, combined interference of the PI3K pathway and the Bcl-2 family of proteins is a reasonable therapeutic strategy. ABT-263 (Navitoclax), an orally available small-molecule Bcl-2 inhibitor, and GDC-0941, a PI3K inhibitor, were used to treat established glioblastoma and glioblastoma neurosphere cells, alone or in combination. Although GDC-0941 alone had a modest effect on cell viability, treatment with ABT-263 displayed a marked reduction of cell viability and induction of apoptotic cell death. Moreover, combinatorial therapy using ABT-263 and GDC-0941 showed an enhanced effect, with a further decrease in cellular viability. Furthermore, combination treatment abrogated the ability of stem cell-like glioma cells to form neurospheres. ABT-263 and GDC-0941, in combination, resulted in a consistent and significant increase of Annexin V positive cells and loss of mitochondrial membrane potential compared with either monotherapy. The combination treatment led to enhanced cleavage of both initiator and effector caspases.

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“…Consistently, a study found that the Notch-1 receptor promotes survival of glioblastoma cells through regulation of Mcl-1 protein, which also mediated by EGFR in transcriptional level. Author further verified that inhibition of the Notch-1 pathway overcomes apoptosis resistance and sensitizes glioblastoma cells to apoptosis induced by ionizing radiation [28]. We measured the expression of EGFR and found that Notch-1 expression positive correlation with the EGFR expression.…”

Section: Discussionmentioning

confidence: 88%

Elevated expression of Notch-1 and EGFR induced apoptosis in glioblastoma multiforme patients

Xing¹,

Sun²,

Guo³

2015

Clinical Neurology and Neurosurgery

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Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1

Cited by 60 publications

References 50 publications

Differential expression of Notch1 intracellular domain and p21 proteins, and their clinical significance in gastric cancer

Differential expression of Notch1 intracellular domain and p21 proteins, and their clinical significance in gastric cancer

PI3K and Bcl-2 Inhibition Primes Glioblastoma Cells to Apoptosis through Downregulation of Mcl-1 and Phospho-BAD

Elevated expression of Notch-1 and EGFR induced apoptosis in glioblastoma multiforme patients

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