Endoplasmic Reticulum (ER) Stress and Hypoxia Response Pathways Interact to Potentiate Hypoxia-inducible Factor 1 (HIF-1) Transcriptional Activity on Targets Like Vascular Endothelial Growth Factor (VEGF)

Background: The UPR and HIF signaling pathways are cytoprotective responses activated by inadequate cellular environments. Results: These pathways can cooperate to increase the expression of shared targets like VEGF. Conclusion: The UPR enhances HIF-1 transcriptional activity. Significance: The simultaneous activation of both pathways in tumors may result in greater vascularization. Cells respond to suboptimal microenvironments by activating stress signaling pathways, like the unfolded protein response and hypoxia-induced transcription factors HIF-1/2, to restore homeostasis. Both cytoprotective pathways have been well studied in isolation at the biochemical and molecular levels. Mounting evidence reveals that they can be activated simultaneously in tumor cells and, likely, in other tissues experiencing inadequate microenvironments and that they share some transcriptional targets, like the proangiogenic factor VEGFA. However, the potential interaction between these pathways is poorly understood. Cell culture experiments revealed that as a consequence of unfolded protein response activation, ATF4 bound to the human VEGFA promoter and activated its transcription, whereas HIF-1 did so in response to hypoxia. When both pathways were activated together, VEGFA transcripts were induced to a higher level than when either stress was applied alone. Surprisingly, this was not due to the combined actions of the stress pathway-specific transcription factors. Instead, we found that endoplasmic reticulum stress potentiated HIF-1 activity to transactivate VEGF expression as well as another well characterized target, BNIP3. These data reveal an unexpected interaction between two important cytoprotective responses that are likely to have significant consequences in environmentally compromised tissues and tumor cells.