Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity.
We have previously shown that radiation increases HIF-1 activity in tumors, causing significant radioprotection of the tumor vasculature. The impact that HIF-1 activation has on overall tumor radiosensitivity, however, is unknown. We reveal here that HIF-1 plays an important role in determining tumor radioresponsiveness through regulating four distinct processes. By promoting ATP metabolism, proliferation, and p53 activation, HIF-1 has a radiosensitizing effect on tumors. Through stimulating endothelial cell survival, HIF-1 promotes tumor radioresistance. As a result, the net effect of HIF-1 blockade on tumor radioresponsiveness is highly dependent on treatment sequencing, with "radiation first" strategies being significantly more effective than the alternative. These data provide a strong rationale for pursuing sequence-specific combinations of HIF-1 blockade and conventional therapeutics.
Moeller
Benjamin J
BJ
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Dreher
Matthew R
MR
Rabbani
Zahid N
ZN
Schroeder
Thies
T
Cao
Yiting
Y
Li
Chuan Y
CY
Dewhirst
Mark W
MW
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000528:radiation effects; D004734:Energy Metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011836:Radiation Tolerance / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000255:Adenosine Triphosphate