scholarly journals PS2 - 194 Bcl-2 Family Member Mcl-1 Expression is Reduced Under Hypoxia by the E3 Ligase FBW7 Contributing to BNIP3 Induced Cell Death In Glioma Cells

2016 ◽  
Vol 43 (S4) ◽  
pp. S14-S14
Author(s):  
Y. Chen ◽  
E. Henson ◽  
E. Shome ◽  
W. Xiao ◽  
D.D. Eisenstat ◽  
...  
Keyword(s):  
Cell Death ◽  
Family Member ◽  
E3 Ligase ◽  
Glioma Cells ◽  
Epidermal Growth Factor Receptors ◽  
Loss Of Function ◽  
Egfr Activation ◽  
A Cell ◽  
Epidermal Growth ◽  
Immunocompromised Mice

Mcl-1 is an anti-apoptotic Bcl-2 family member that is often over-expressed in the malignant brain tumour glioblastoma (GBM). It has been previously shown that epidermal growth factor receptors (EGFR) up-regulate Mcl-1 expression contributing to a cell survival response. Hypoxia is a poor prognostic marker in glioblastoma despite the fact that hypoxic regions have areas of necrosis. Hypoxic regions of GBM also highly express the pro-cell death Bcl-2 family member BNIP3, yet when BNIP3 is over-expressed in glioma cells, it induces cell death. The reasons for this discrepancy are unclear. METHODS: Using malignant glioma cell lines +/- hypoxia, gain and/or loss of function assays of BNIP3 or Mcl-1 were performed. BNIP3 and MCL-1 expression was assessed in GBM tumours from adult patients and human gliomas grown as xenografts in immunocompromised mice. RESULTS: Mcl-1 expression is reduced under hypoxia due to degradation by the E3 ligase FBW7 leading to increased hypoxia-induced cell death. This cell death is augmented by EGFR activation leading to increased Mcl-1 expression under hypoxia. Conversely, BNIP3 is over-expressed in hypoxia at times when Mcl-1 expression is decreased. Knocking down BNIP3 expression reduces hypoxia cell death and Mcl-1 expression effectively blocks BNIP3-induced cell death. Of significance, BNIP3 and Mcl-1 are co-localized under hypoxia in glioma cells, GBM tumours and in xenograft glioma tumours expressing mutant EGFR (EGFRvIII). CONCLUSION: These results support that Mcl-1 can block the ability of BNIP3 to induce cell death under hypoxia in GBM tumours

scholarly journals CBIO-10Bcl-2 FAMILY MEMBER Mcl-1 EXPRESSION IS REDUCED UNDER HYPOXIA BY THE E3 LIGASE FBW7 CONTRIBUTING TO BNIP3 INDUCED CELL DEATH IN GLIOMA CELLS

2015 ◽  
Vol 17 (suppl 5) ◽  
pp. v57.1-v57
Author(s):  
Yongqiang Chen ◽  
Elizabeth Henson ◽  
Epsita Shome ◽  
Wenyan Xiao ◽  
David Eisenstat ◽  
...  
Keyword(s):  
Cell Death ◽  
Family Member ◽  
E3 Ligase ◽  
Glioma Cells

scholarly journals Bcl-2 family member Mcl-1 expression is reduced under hypoxia by the E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells

2015 ◽  
Vol 17 (6) ◽  
pp. 604-613 ◽  
Author(s):  
Yongqiang Chen ◽  
Elizabeth S. Henson ◽  
Wenyan Xiao ◽  
Epsita Shome ◽  
Meghan B. Azad ◽  
...  
Keyword(s):  
Cell Death ◽  
Family Member ◽  
E3 Ligase ◽  
Glioma Cells

A Conjugate of an Anti-Epidermal Growth Factor Receptor (EGFR) VHH and a Cell-Penetrating Peptide Drives Receptor Internalization and Blocks EGFR Activation

ChemBioChem ◽  
2017 ◽  
Vol 18 (24) ◽  
pp. 2390-2394 ◽  
Author(s):  
Sanne A. M. van Lith ◽  
Dirk van den Brand ◽  
Rike Wallbrecher ◽  
Sander M. J. van Duijnhoven ◽  
Roland Brock ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Receptor Internalization ◽  
Cell Penetrating Peptide ◽  
Egfr Activation ◽  
Cell Penetrating ◽  
A Cell ◽  
Epidermal Growth

scholarly journals Autophagy as a Potential Therapy for Malignant Glioma

2020 ◽  
Vol 13 (7) ◽  
pp. 156 ◽  
Author(s):  
Angel Escamilla-Ramírez ◽  
Rosa A. Castillo-Rodríguez ◽  
Sergio Zavala-Vega ◽  
Dolores Jimenez-Farfan ◽  
Isabel Anaya-Rubio ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Tumor Cells ◽  
Glioma Cells ◽  
High Grade ◽  
Therapeutic Approaches ◽  
Genetic Changes ◽  
A Cell ◽  
Autophagic Process ◽  
Marked Resistance

Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, radiation, chemotherapy, and immunotherapy. The resistance of GBM to various therapies is due to a highly mutated genome; these genetic changes induce a de-regulation of several signaling pathways and result in higher cell proliferation rates, angiogenesis, invasion, and a marked resistance to apoptosis; this latter trait is a hallmark of highly invasive tumor cells, such as glioma cells. Due to a defective apoptosis in gliomas, induced autophagic death can be an alternative to remove tumor cells. Paradoxically, however, autophagy in cancer can promote either a cell death or survival. Modulating the autophagic pathway as a death mechanism for cancer cells has prompted the use of both inhibitors and autophagy inducers. The autophagic process, either as a cancer suppressing or inducing mechanism in high-grade gliomas is discussed in this review, along with therapeutic approaches to inhibit or induce autophagy in pre-clinical and clinical studies, aiming to increase the efficiency of conventional treatments to remove glioma neoplastic cells.

scholarly journals Activation of Epidermal Growth Factor Receptor Sensitizes Glioblastoma Cells to Hypoxia-Induced Cell Death

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2144
Author(s):  
Anna-Luisa Luger ◽  
Nadja I. Lorenz ◽  
Hans Urban ◽  
Iris Divé ◽  
Anna L. Engel ◽  
...  
Keyword(s):  
Cell Death ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Atp Depletion ◽  
Metabolic Effects ◽  
Metabolic Adaptation ◽  
Egfr Activation ◽  
Epidermal Growth

Background: The epidermal growth factor receptor (EGFR) signaling pathway is genetically activated in approximately 50% of glioblastomas (GBs). Its inhibition has been explored clinically but produced disappointing results, potentially due to metabolic effects that protect GB cells against nutrient deprivation and hypoxia. Here, we hypothesized that EGFR activation could disable metabolic adaptation and define a GB cell population sensitive to starvation. Methods: Using genetically engineered GB cells to model different types of EGFR activation, we analyzed changes in metabolism and cell survival under conditions of the tumor microenvironment. Results: We found that expression of mutant EGFRvIII as well as EGF stimulation of EGFR-overexpressing cells impaired physiological adaptation to starvation and rendered cells sensitive to hypoxia-induced cell death. This was preceded by adenosine triphosphate (ATP) depletion and an increase in glycolysis. Furthermore, EGFRvIII mutant cells had higher levels of mitochondrial superoxides potentially due to decreased metabolic flux into the serine synthesis pathway which was associated with a decrease in the NADPH/NADP+ ratio. Conclusions: The finding that EGFR activation renders GB cells susceptible to starvation could help to identify a subgroup of patients more likely to benefit from starvation-inducing therapies.

scholarly journals Recruitment of epidermal growth factor receptors into coated pits requires their activated tyrosine kinase.

1995 ◽  
Vol 129 (1) ◽  
pp. 47-54 ◽  
Author(s):  
C Lamaze ◽  
S L Schmid
Keyword(s):  
Tyrosine Kinase ◽  
Egf Receptor ◽  
Epidermal Growth Factor Receptors ◽  
Deletion Mutants ◽  
Functional Assay ◽  
Wild Type ◽  
Coated Pits ◽  
Kinase Substrate ◽  
A Cell ◽  
Epidermal Growth

EGF-receptor (EGF-R) tyrosine kinase is required for the down-regulation of activated EGF-R. However, controversy exists as to whether ligand-induced activation of the EGF-R tyrosine kinase is required for internalization or for lysosomal targeting. We have addressed this issue using a cell-free assay that selectively measures the recruitment of EGF-R into coated pits. Here we show that EGF bound to wild-type receptors is efficiently sequestered in coated pits. In contrast, sequestration of kinase-deficient receptors occurs inefficiently and at the same basal rate of endocytosis of unoccupied receptors or receptors lacking any cytoplasmic domain. Sequestration of deletion mutants of the EGF-R that lack autophosphorylation sites also requires an active tyrosine kinase. This suggests that a tyrosine kinase substrate(s) other than the EGF-R itself, is required for its efficient ligand-induced recruitment into coated pits. Addition of a soluble EGF-R tyrosine kinase fully and specifically restores the recruitment of kinase-deficient EGF-R into coated pits providing a powerful functional assay for identification of these substrate(s).

scholarly journals Interferometric scattering microscopy reveals microsecond nanoscopic protein motion on a live cell membrane

2018 ◽  
Author(s):  
Richard W. Taylor ◽  
Reza Gholami Mahmoodabadi ◽  
Verena Rauschenberger ◽  
Andreas Giessl ◽  
Alexandra Schambony ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Particle Tracking ◽  
Three Dimensions ◽  
Epidermal Growth Factor Receptors ◽  
Biological Functions ◽  
Time Intervals ◽  
A Cell ◽  
Epidermal Growth

AbstractMuch of the biological functions of a cell are dictated by the intricate motion of proteins within its membrane over a spatial range of nanometers to tens of micrometers and time intervals of microseconds to minutes. While this rich parameter space is not accessible to fluorescence microscopy, it can be within reach of interferometric scattering (iSCAT) particle tracking. Being sensitive even to single unlabeled proteins, however, iSCAT is easily accompanied by a large speckle-like background, which poses a substantial challenge for its application to cellular imaging. Here, we show that these difficulties can be overcome and demonstrate tracking of transmembrane epidermal growth factor receptors (EGFR) with nanometer precision in all three dimensions at up to microsecond speeds and tens of minutes duration. We provide unprecedented examples of nanoscale motion and confinement in ubiquitous processes such as diffusion in the plasma membrane, transport on filopodia, and endocytosis.

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