Host: The Japan Radiation Research Society
Purpose:
Tumor microenvironment is dramatically altered after radiotherapy. Hypoxia-inducible Factor-1 (HIF-1), in response to the alteration, promotes tumor radioresistance by inducing various gene expressions. The purpose of this study is to analyze the postirradiation dynamism of intratumoral HIF-1 activity and the underlying molecular mechanisms.
Methods: Subcutaneous tumor xenografts with a novel HIF-1-dependent reporter gene were locally irradiated with 5 Gy of gamma-ray. The postirradiation change of intratumoral HIF-1 activity was optically imaged as the HIF-1-dependent bioluminescence.
Results:
Intratumoral HIF-1 activity was transiently decreased 6 h postirradiation in response to radiation-induced reoxygenation of hypoxic tumor cells. Later, the HIF-1 activity turned to increase, although the cells were still re-oxygenated. The former decrease of HIF-1 activity was suppressed in the von Hippel-Lindau (VHL)-deficient cell line. On the other hand, the later increase was suppressed by PI3K/Akt/mTOR pathway-inhibitors (LY294002 and rapamycin) or a non-metabolizable glucose analog (2-deoxy-D-glucose). In vitro studies confirmed that just after reoxygenation treatment, addition of glucose dramatically accelerated HIF-1alpha translation in PI3K/Akt/mTOR-dependent manner.
Conclusion:
After irradiation, intratumoral HIF-1 activity transiently decreases via VHL-dependent degradation of HIF-1alpha protein and subsequently increases via glucose-dependent up-regulation of HIF-1alpha translation. Therefore, we propose here that the that alteration of tumor microenvironments influences HIF-1 activity after irradiation; in postirradiation reoxygenation in early phase- and re-glucose (improvement of glucose distribution to hypoxic cells) in late phase conditions, respectively. To our knowledge, this is the first report emphasizing the importance of radiation-induced alteration of glucose- as well as hypoxic-microenvironment in the regulation of intratumoral HIF-1 activity.
