title: Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity.
abstract: 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.
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Moeller
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Dreher
authors.forename: Zahid N
authors.initials: ZN
authors.lastname: Rabbani
authors.forename: Thies
authors.initials: T
authors.lastname: Schroeder
authors.forename: Yiting
authors.initials: Y
authors.lastname: Cao
authors.forename: Chuan Y
authors.initials: CY
authors.lastname: Li
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: 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
chemical_list: 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