The
mammalian target of rapamycin (mTOR) regulates cellular growth and proliferation, mainly by controlling cellular translation. Most
tumors show constitutive activation of the mTOR pathway. In
hypoxia, mTOR is inactivated, which is believed to be part of the program of the cell to maintain energy homeostasis. However, certain
proteins are believed to be preferentially translated during
hypoxia via 5' terminal oligopyrimidine tract mechanisms with controversial discussion about the involvement of the mTOR-dependent
ribosomal protein S6 (rpS6). The
hypoxia-inducible
transcription factor (HIF) is the master regulator of hypoxic adaptation and itself strongly implicated in
tumor growth. HIF is translationally regulated by mTOR. The regulatory features and the involvement of molecular
oxygen itself in this regulation of HIF by mTOR are poorly understood. mTOR inhibition leads to profound attenuation of HIFalpha
protein in the majority of primary and
cancer cells studied. Under severe
hypoxia, no influence of
mTOR inhibitors was observed; thus, stimulation of HIFalpha by mTOR may only be relevant under mild
hypoxia or even normoxia. HIF expression and phosphorylated rpS6 negatively correlate in experimental
tumors. In cell culture, prolonged
hypoxia abolishes rpS6 phosphorylation, which seems to be partly independent of the upstream p70S6
kinase. We show that hypoxic repression of rpS6 is largely dependent on HIF, implicating a negative feedback loop, which may influence cellular translational rates and metabolic homeostasis. These data implicate that the hypoxic microenvironment renders
tumor cells resistant to mTOR inhibition, at least concerning hypoxic gene activation, which would add to the difficulties of other established therapeutic strategies in hypoxic
cancer tissues.