HIF2alpha inhibition promotes p53 pathway activity, tumor cell death, and radiation responses.
Approximately 50% of cancer patients receive radiation treatment, either alone or in combination with other therapies. Tumor hypoxia has long been associated with resistance to radiation therapy. Moreover, the expression of hypoxia inducible factors HIF1alpha and/or HIF2alpha correlates with poor prognosis in many tumors. Recent evidence indicates that HIF1alpha expression can enhance radiation-induced apoptosis in cancer cells. We demonstrate here that HIF2alpha inhibition promotes tumor cell death and, in contrast to HIF1alpha, enhances the response to radiation treatment. Specifically, inhibiting HIF2alpha expression augments p53 activity, increases apoptosis, and reduces clonogenic survival of irradiated and non-irradiated cells. Moreover, HIF2alpha inhibition promotes p53-mediated responses by disrupting cellular redox homeostasis, thereby permitting reactive oxygen species (ROS) accumulation and DNA damage. These results correlate with altered p53 phosphorylation and target gene expression in untreated human tumor samples and show that HIF2alpha likely contributes to tumor cell survival including during radiation therapy.
Bertout
Jessica A
JA
Abramson Family Cancer Research Institute, Abramson Cancer Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Majmundar
Amar J
AJ
Gordan
John D
JD
Lam
Jennifer C
JC
Ditsworth
Dara
D
Keith
Brian
B
Brown
Eric J
EJ
Nathanson
Katherine L
KL
Simon
M Celeste
MC
D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000528:radiation effects; D016923:Cell Death / Q000528:radiation effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004249:DNA Damage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D000099162:Endothelial PAS Domain-Containing Protein 1; C438378:BBC3 protein, human
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