Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules.

Published

Journal Article

Through a poorly understood mechanism, tumors respond to radiation by secreting cytokines capable of inhibiting apoptosis in endothelial cells, thereby diminishing treatment response by minimizing vascular damage. We reveal here that this pathway is governed by a major angiogenesis regulator, HIF-1. Following radiotherapy, tumor reoxygenation leads to: (1) nuclear accumulation of HIF-1 in response to reactive oxygen, and (2) enhanced translation of HIF-1-regulated transcripts secondary to stress granule depolymerization. The resulting increase in HIF-1-regulated cytokines enhances endothelial cell radioresistance. Inhibiting postradiation HIF-1 activation significantly increases tumor radiosensitivity as a result of enhanced vascular destruction. These data describe novel pathways contributing significantly to our understanding of HIF-1 regulation which may be major determinants of tumor radiosensitivity, potentially having high clinical relevance.

Full Text

Duke Authors

Cited Authors

  • Moeller, BJ; Cao, Y; Li, CY; Dewhirst, MW

Published Date

  • May 2004

Published In

Volume / Issue

  • 5 / 5

Start / End Page

  • 429 - 441

PubMed ID

  • 15144951

Pubmed Central ID

  • 15144951

Electronic International Standard Serial Number (EISSN)

  • 1878-3686

International Standard Serial Number (ISSN)

  • 1535-6108

Digital Object Identifier (DOI)

  • 10.1016/s1535-6108(04)00115-1

Language

  • eng