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

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.

A Novel Radiotherapeutic Approach to Treat Bulky Metastases Even From Cutaneous Squamous Cell Carcinoma: Its Rationale and a Look at the Reliability of the Linear-Quadratic Model to Explain Its Radiobiological Effects

“…It is reasonable to assume that between normoxic and necrotic areas, hypoxic cell clones exist. These cells, for example, through—but not only—the hypoxia-inducible factor 1α (HIF-1α) signaling pathway, develop a metabolic adaptation to hypoxia and survive ( 43 ). They may be not actively proliferating but still viable and able to escape from the radiation effects.…”

LncRNA MALAT1 Promotes PPARα/CD36-Mediated Hepatic Lipogenesis in Nonalcoholic Fatty Liver Disease by Modulating miR-206/ARNT Axis

“…ARNT, also known as HIF-1β, forming a complex with HIF-1α participates in the emergency response under hypoxic conditions ( Smythies et al, 2019 ). In general, ARNT expression is located in the nucleus, and it forms dimers with HIF-1α under hypoxic conditions, to regulate physiological processes such as angiogenesis and energy metabolism as transcription factor ( Lee et al, 2021 ). Hoang et al showed that ARNT was expressed in islet beta cells.…”

Genetic analysis and clinical significance of a rare t(1;12)(q21;p13) in a patient with high‐risk myelodysplastic syndrome

“…Translocation resulting from the break apart of 12p13 usually involves ETV6 gene in hematologic malignancies, such as t (5;12) (q31‐33; p13) in chronic myelomonocytic leukemia (Apperley et al, 2002; Di Giacomo et al, 2021) and t (12;21) (p13;q22) in ALL (Montaño et al, 2020; Shurtleff et al, 1995). The aryl hydrocarbon receptor nuclear translocator ( ARNT ) gene, also named HIF‐1β , locates in 1q21, which play a critical role in driving tumor growth and metastasis (Lee et al, 2021). It has been reported as a partner gene of fusion gene in two cases with t(1,12)(q21;p13)(Otsubo et al, 2010; Salomon‐Nguyen et al, 2000).…”