The Akt/mTOR Pathway Assures the Synthesis of HIF-1α Protein in a Glucose- and Reoxygenation-dependent Manner in Irradiated Tumors

Abstract

Transcriptional activity of HIF-1 (hypoxia-inducible factor-1) has been reported to be up-regulated in solid tumors after ionizing radiation; however, the molecular mechanism underlying the response remains to be elucidated. In the present study, we performed a series of molecular imaging experiments using a HIF-1-dependent reporter gene, 5HREp-ODD-luc, and found an essential role of the Akt/mTOR pathway. Hypoxic tumor cells distant from blood vessels and HIF-1 activity in the a the of of in the and an the of the Akt/mTOR in the of In experiments an in and up-regulated the and the reported of essential to the of of of a role in the of HIF-1 activity in response to of and in a solid Transcriptional activity of HIF-1 (hypoxia-inducible factor-1) has been reported to be up-regulated in solid tumors after ionizing radiation; however, the molecular mechanism underlying the response remains to be elucidated. In the present study, we performed a series of molecular imaging experiments using a HIF-1-dependent reporter gene, 5HREp-ODD-luc, and found an essential role of the Akt/mTOR pathway. Hypoxic tumor cells distant from blood vessels and HIF-1 activity in the a the of of in the and an the of the Akt/mTOR in the of In experiments an in and up-regulated the and the reported of essential to the of of of a role in the of HIF-1 activity in response to of and in a solid and of cells and to an of and in solid a of from tumor blood vessels the of and to and after the tumor cells tumor blood vessels to a in has been of the tumor has been reported the of from tumor blood vessels to tumor cells after a of the of tumor cells and a in in cells tumor and has been the of (hypoxia-inducible a to to the of tumors HIF-1 a of an and a and activity the and of the the of and a in of the the and and to the and the of reported to cells from the of and tumor to in HIF-1 activity after and the underlying molecular found HIF-1 activity to after of an mechanism in the the molecular the of HIF-1 activity has been the present study, we HIF-1 activity in a tumor a reporter in an the of a HIF-1-dependent the and HIF-1-dependent of the and of the the reporter to HIF-1 activity in imaging experiments and we the of HIF-1 activity the of in of of the solid we found the Akt/mTOR an essential role in the of in a and we the Akt/mTOR and the reported mechanism the of and the of the and in the of from the and in cells in a and cells in a of and in and the of and in experiments and and cells cells the the and in to in the to the of in the in in and the the using to the cells an to the of the and to and the to a a and in and to cells and of of performed using to the and performed using and using and an to the the of the cells in the to using a to the performed using an the using a and and a in cells in cells in the of and after in to to the of the in the the of the after the cells in cells in the of an and after the in to and a and a and and and and in the to cells and a of and the of after cells and in cells in in the of and and and and after the in to and after in the cells a to and of cells the of the tumor the tumor of using a of tumor a in cells a of an after in and the the tumor to the in and and in the and the in the the of and and the of of of the of and in tumor and the using of and the in a and the of in the tumor an of in the of in a an in imaging to the an in imaging the the in the using In imaging and of of experiments the of and in in after the of ionizing HIF-1 we a HIF-1-dependent reporter gene, 5HREp-ODD-luc, in the of the reported reporter the imaging of HIF-1 activity in tumor cells the and the of HIF-1 activity using an in imaging we HIF-1 activity and and the the tumor the gene, after the and the in from the and using the tumor the of the of after the and and the in of the cells the in the to be the in HIF-1 activity in tumor and HIF-1 activity after ionizing a of HIF-1 activity the after and the and after the in and the to the the tumor after a of and to to the of and of cells and cells in of the and a after a of HIF-1 activity the of we 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tumor of HIF-1 activity after in the tumor and in the tumors of to a in the of in the and of the of the Akt/mTOR in the of and HIF-1 activity in solid the of and HIF-1 activity after the a of HIF-1 activity the after the and after the in and the to the after the a of and to of cells in Akt/mTOR an essential role in the of and HIF-1 activity and a of HIF-1 activity the after the and after the in and the to the and after the a of and to of cells in of and the of the present study, we the of and the Akt/mTOR in the of in of solid the in of in the of and the of in the of reported to and to the the and the of the of the of the of we the an of we a to the in in the cells and the to the of and of the to the of and the of in to the of and of and in of and in the of in the in a of and and of and of in the and of and essential the of in a the of the and the Akt/mTOR in the of HIF-1 in we using and In cells in cells the of and the in in in and of and of the of and to the of the of in a and in of 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In in experiments the of in a and of the of and to the of the of of solid has been cells from tumor blood vessels we the of in the of HIF-1 activity in HIF-1 activity in in and HIF-1 in of the of and HIF-1 in the of in the response the of in solid tumors the of in the of HIF-1 to the of in solid tumors after a using has been the using an the of and we be to the of the of and HIF-1 activity In in the of after and to the of and the in mechanism underlying the remains to be however, of the in to of the of the of in the of and the present study, the of the of HIF-1 be the of In the of in tumor cells the of the of in the of in to in the after of the of the of to a in in the essential the of and of the of after in in the of and to the of reported to the of and in the and of the we and of an role in the the and the of has been however, we the in the of after in in in the of the of and of the of the of the the of be the of HIF-1 In and of the of HIF-1 activity in in and in present the of an mechanism In cells the cells in the solid tumor of the of in tumor of the Akt/mTOR in of solid the in in the in to the and of the of in the the Akt/mTOR in of of of the tumor and the mechanism of from an to an present a of the mechanism the tumor after the tumor and the tumor cells in a and tumor has been a however, the molecular mechanism the present the of after we the tumor cells and of tumor after and in we of the Akt/mTOR in the cells the tumor the of cells after of Akt/mTOR be the of a molecular the to the of in the of HIF-1 in solid the present the of the tumor and in the of HIF-1 present to of using a tumor in a tumor of blood of of a to be from of to and