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

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 9; p. 2371
• Main Authors: Lee, Shen-Han, Golinska, Monika, Griffiths, John R.
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 09.09.2021; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenosine triphosphate; AKT protein; AMP-activated protein kinase; Angiogenesis; Autophagy; Binding sites; Cancer; cancer metabolism; Carbohydrate metabolism; Clinical trials; Creatine; creatine metabolism; Dehydrogenases; Drug resistance; Enzymes; Epigenetics; Genomics; Glucose; Glucose metabolism; Glutamine; glycolysis; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-inducible factor 1a; hypoxia-inducible factor-1 (HIF-1); Kinases; Lipid metabolism; Metabolism; Metastasis; Microenvironments; Myc; Myc protein; Phosphorylation; Post-translation; Protein turnover; Review; Signal transduction; Solid tumors; Transcription factors; Tumors
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10092371

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.