HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells.


Type
Article
Change log
Authors
Golinska, Monika 
Abstract

In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.

Description
Keywords
Hypoxia, MYC, lipid metabolism, glycolysis, Cancer Metabolism, Glutamine Metabolism, Amp-activated Protein Kinase (Ampk), 2-Hydroxyglutarate, Phosphatidylinositol 3-Kinase (Pi3k), Hypoxia-inducible Factor-1 (Hif-1), Creatine Metabolism
Journal Title
Cells
Conference Name
Journal ISSN
2073-4409
Volume Title
10
Publisher