Hypoxia is a common phenomenon in human solid
tumors and has been considered as an important, independent negative prognostic factor for response to treatment and survival of
tumor patients.
Hypoxia-inducible factor-1 (HIF-1) is the central
transcription factor which is activated by
hypoxia and modulates the expression of many genes involved in cell metabolism, proliferation, apoptosis, angiogenesis. Recently, it has been reported that HIF-1 contributes to
tumor radioresistance by upregulating
survivin expression under hypoxic conditions. Moreover, in hypoxic
tumor cells, HIF-1 dependent signal transduction pathway is activated and could be further enhanced by radiation, thereby providing survival signals to adjacent vascular endothelial cells by upregulation of
VEGF and bFGF and resulting in
tumor radioresistance through vascular radioprotection. Recent research revealed that the stability of HIF-1alpha, one of the two subunits of HIF-1, determines the whole HIF-1 activity and the C-terminal transactivation domain of HIF-1alpha could reduce HIF-1 activity when overexpressed in
tumor cells by disruption of the assembly of HIF-1 transcription complex. Therefore, we postulate that fusion with
protein transduction domains would overcome the inability of C-terminal transactivation domain of HIF-1alpha to cross cellular membrane. Thus the
recombinant fusion proteins could serve as cell-permeable HIF-1 antagonists, function as both inhibitors of
tumor angiogenesis and
tumor radiosensitizers, and would be widely used in clinical settings to improve
tumor response to
radiotherapy.