RESUMO
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.
Assuntos
Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Astrócitos/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Morte Celular/genética , Diferenciação Celular , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Camundongos , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , RNA Interferente Pequeno/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/antagonistas & inibidores , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transcrição GênicaRESUMO
Bcl-2 nineteen-kilodalton interacting protein (BNIP3) is a BH-3-only Bcl-2 family member whose expression levels increase during stress such as hypoxia through hypoxia-inducing factor-1-dependent or -independent mechanisms. When BNIP3 expression is induced, it localizes to the mitochondria and triggers a loss of membrane potential, and an increase in the reactive oxygen species production, which often leads to cell death. Cells under normal growth conditions suppress BNIP3 expression through transcriptional repression. There is considerable debate in the literature regarding what type of cell death is induced by BNIP3. It has been observed that BNIP3 could induce necrosis, autophagy and/or apoptosis. In contrast, other studies indicate that BNIP3 could promote cell survival. Besides its cell death regulation, BNIP3 plays a key role in the pathogenicity of many diseases. In cardiac infarction, loss of BNIP3 expression has been shown to reduce the number of damaged cardiomyocytes after ischemia and reperfusion. BNIP3 expression also plays an important role in the deregulation of cell death in many cancers. In this review, we will discuss the different and often contradictory mechanisms of BNIP3 regulation of cell death and the role that BNIP3 may play in diseases.
