Abstract
Glioblastoma multiforme (GBM) is the most common and malignant brain tumor, and current treatment modalities such as surgical resection, adjuvant radiotherapy and temozolomide (TMZ) chemotherapy are ineffective. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel cancer therapeutic agent for GBM because of its capability of inducing apoptosis in glioma cells. Unfortunately, the majority of glioma cells are resistant to TRAIL-induced apoptosis. The Bcl-2 nineteen kilodalton interacting protein (BNIP3) is a pro-cell death BH3-only member of the Bcl-2 family that is one of the highest expressed genes in hypoxic regions of GBM tumors. We previously found that BNIP3 is localized to the nucleus in GBM tumors and suppresses cell death in glioma cells. Herein, we have discovered when BNIP3 nuclear expression is knockdown in glioma cell lines and in normal mouse astrocytes, TRAIL and its death receptor, death receptor-5 (DR5) expression is increased. In addition, when nuclear BNIP3 expression is increased, the amount of TRAIL-induced apoptosis is reduced. Using a streptavidin pull-down assay, we found that BNIP3 binds to the DR5 promoter and nuclear BNIP3 binds to the DR5 promoter. Furthermore, nuclear BNIP3 expression in GBM tumors correlates with decreased DR5 expression. Taken together, we have discovered a novel transcriptional repression function for BNIP3 conferring a TRAIL resistance in glioma cells.
Highlights
Tumor necrosis-related apoptosis-inducing ligand (TRAIL/ Apo-2 L) binds to death receptor-4 (DR4, TRAIL-R1) and death receptor-5 (DR5, TRAIL-R2)
We have previously identified that Bcl-2 nineteen kilodalton interacting protein 3 (BNIP3) is expressed in the nucleus of primary human astrocytes and glioma cell lines, and it transcriptionally represses the expression of AIF.[28]
We found that DR5 expression significantly increased in cells lacking BNIP3 expression, whereas TRAIL, DR4, caspase 8, caspase 3, Bcl-xL and FLIP expression remained unchanged
Summary
Tumor necrosis-related apoptosis-inducing ligand (TRAIL/ Apo-2 L) binds to death receptor-4 (DR4, TRAIL-R1) and death receptor-5 (DR5, TRAIL-R2) This lead to the activation of caspase 8 and subsequent cleavage of the Bcl-2 BH3-only family member BID causing mitochondrial dysfunction and apoptosis. The Bcl-2 nineteen kilodalton interacting protein 3 (BNIP3) is a pro-cell death Bcl-2 family that is upregulated during hypoxia.[20] When BNIP3 is upregulated, it induces caspaseindependent cell death by localizing to the mitochondria and opening the permeability transition pore leading to loss of mitochondrial membrane potential (Dcm) and reactive oxygen species production.[20,21] Recently, studies have implicated BNIP3 in the induction of autophagic cell death (programmed cell death type II) in malignant gliomas in response to hypoxia and arsenic trioxide treatment.[22,23] BNIP3 is directly upregulated under hypoxic conditions by the transcription factor HIF-1, contributing to hypoxia-induced cell death.[24,25,26] Paradoxically, BNIP3 is expressed at high levels in viable cells within hypoxic regions of tumors.[27] This is partially due to nuclear localization of BNIP3 in tumors where BNIP3 fails to associate with the mitochondria, and promote cell death.[28] This nuclear localization allows BNIP3 to associate with various promoters and repress their expression. We have found that BNIP3 binds to and represses the expression of apoptosis-inducing factor (AIF-1), contributing to resistance against TMZ-induced apoptosis.[29]
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