Etiology and Pathogenesis > Epidermal Growth Factor · Hypoxia · Invasion | Treatment > Chemoresistance

Meeting Abstract

T. Burton, P. Baijal, E. Henson, S. Zhang, S.B. Gibson, and D.D. Eisenstat

Manitoba Institute of Cell Biology, Departments of Biochemistry & Medical Genetics, Pediatrics, Anatomy and Physiology, University of Manitoba, Winnipeg, MB, Canada

Astrocytic tumors are the most common form of brain tumor in children and adults.
Glioblastoma multiforme (GBM, WHO grade IV) represents the most malignant form of astrocytoma with a time to progression of 12 weeks without therapeutic intervention and 12 to 15 months of survival with combined modality therapy, including surgery, radiation, and chemotherapy.
Response to therapy fails, in part, due to tumor hypoxia facilitating resistance to radiation and chemotherapy.
The BCL2-Nineteen Kilodalton Interacting protein, BNIP3, is a pro-apoptotic Bcl-2 family member that binds to mitochondria via its transmembrane domain (TMD).
BNIP3 is upregulated in hypoxic regions in many solid tumors.
Upon overexpression, BNIP3 induces cell death in a caspase-independent manner.
In this study we have determined that BNIP3 expression is upregulated in GBM compared to normal brain.
BNIP3 co-localizes with GFAP in malignant astrocytes.
This increased expression in GBM correlates with increased expression of the transcription factor HIF-1α that is an indicator for hypoxic regions in tumors.
In glioma cell lines, both BNIP3 and HIF-1α expression increase under hypoxic conditions over a 72-hour time course.
The BNIP3 promoter contains hypoxia response elements (HREs) regulated by HIF-1α and, when transfected under hypoxic conditions, the promoter is activated (Kothari et al., 2003).
Overexpression of BNIP3 into malignant glioma cells induces cell death, whereas expression of a dominant negative form of BNIP3 with deletion of the TMD blocks hypoxia-induced cell death.
Of interest, BNIP3 colocalizes with mitochondria in malignant glioma cell lines under hypoxic conditions but does not co-localize with mitochondria in GBM tumors.
Since we have demonstrated that BNIP3 is expressed in viable cells within GBM tumors, and BNIP3 plays a role in hypoxia-induced cell death in glioma cells, there may be a survival mechanism preventing BNIP3-induced cell death in GBM tumors.
Primary (de novo) GBM is marked by epidermal growth factor receptor (EGFR) amplification, and activation of EGFR promotes cell survival.
To determine whether EGF protects against BNIP3-induced cell death, we treated malignant glioma cells with EGF.
This treatment effectively inhibited BNIP3-induced cell death due to inhibition of BNIP3-mediated mitochondrial dysfunction, such as changes in membrane potential.
Although BNIP3 is upregulated in GBM under hypoxic conditions mediated by HIF-1α, EGFR might provide a protective effect promoting cell survival.
This could provide a mechanism to explain why treatments for malignant gliomas are often ineffective in hypoxic regions of these tumors.

This study was supported by CancerCare Manitoba.

Copyright © 2003 by the Society for Neuro-Oncology