BNIP3 plays a role in hypoxic cell death in human epithelial cells that is inhibited by growth factors EGF and IGF

Autor: Spencer B. Gibson, Eileen M. McMillan-Ward, Michelle Bailes, Shilpa Kothari, Karen Ens, Lorrie A. Kirshenbaum, Sara J. Israels, Jeannick Cizeau
Rok vydání: 2003
Předmět:
Cancer Research
Time Factors
medicine.medical_treatment
Apoptosis
Hypoxic cell
Genes
Reporter
Cricetinae
Tumor Cells
Cultured
Insulin-Like Growth Factor I
Hypoxia
Promoter Regions
Genetic
Genes
Dominant
Cell Death
Cell biology
medicine.anatomical_structure
medicine.symptom
Cell Division
hormones
hormone substitutes
and hormone antagonists
Signal Transduction
medicine.medical_specialty
Programmed cell death
Blotting
Western
CHO Cells
Biology
Transfection
Cell Line
Proto-Oncogene Proteins
Internal medicine
Genetics
medicine
Animals
Humans
Molecular Biology
Fluorescent Dyes
Epidermal Growth Factor
Tumor Suppressor Proteins
Growth factor
Membrane Proteins
Epithelial Cells
Trypan Blue
Oligonucleotides
Antisense
Hypoxia (medical)
Hypoxia-Inducible Factor 1
alpha Subunit
beta-Galactosidase
Acridine Orange
Epithelium
Protein Structure
Tertiary
Microscopy
Electron
Endocrinology
Mutation
Transcription Factors
Zdroj: Oncogene. 22:4734-4744
ISSN: 1476-5594
0950-9232
DOI: 10.1038/sj.onc.1206666
Popis: Hypoxic regions within solid tumors are often resistant to chemotherapy and radiation. BNIP3 (Bcl-2/E1B 19 kDa interacting protein) is a proapoptotic member of the Bcl-2 family that is expressed in hypoxic regions of tumors. During hypoxia, BNIP3 expression is increased in many cell types and upon forced overexpression BNIP3 induces cell death. Herein, we have demonstrated that blockage of hypoxia-induced BNIP3 expression using antisense oligonucleotides against BNIP3 or blockage of BNIP3 function through expression of a mutant form of BNIP3 inhibits hypoxia-induced cell death in human embryonic kidney 293 cells. We have also determined that hypoxia-mediated BNIP3 expression is regulated by the transcription factor, hypoxia-inducible factor-1alpha (HIF-1alpha) in human epithelial cell lines. Furthermore, HIF-1alpha directly binds to a consensus HIF-1alpha-responsive element (HRE) in the human BNIP3 promoter that upon mutation of this HRE site eliminates the hypoxic responsiveness of the promoter. Since BNIP3 is expressed in hypoxic regions of tumors but fails to induce cell death, we determined whether growth factors block BNIP3-induced cell death. Treatment of the breast cancer cell line MCF-7 cells with epidermal growth factor (EGF) or insulin-like growth factor effectively protected these cells from BNIP3-induced cell death. Furthermore, inhibiting EGF receptor signaling using antibodies against ErbB2 (Herceptin) resulted in increased hypoxia-induced cell death in MCF-7 cells. Taken together, BNIP3 plays a role in hypoxia-induced cell death in human epithelial cells that could be circumvented by growth factor signaling.
Databáze: OpenAIRE
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