An ever-increasing number of scientific papers are being produced that highlight the effects and importance of hypoxia in various research fields. Dr Burga Kalz Fuller, Product Manager at our American distributor, HypOxygen, has summarised five interesting and recent papers concerning hypoxia and its role in cancer metabolism research:
In this paper, the role of hypoxia – as mediated by HIF, interfacing with many different oncogenic pathways – is reviewed. Activated HIF both suppresses mitochondrial metabolism and up-regulates biosynthesis of intermediates needed by proliferating cells in cancer. Complex relationships between HIF activation and cancer phenotype are discussed in detail by these Oxford UK researchers.
A new mechanism whereby activated HIF-1 affects tumor metabolism through reduced activity of the mitochondrial α ketoglutarate dehydrogenase (aKGDH), is described in this short paper. Targeted mutagenesis of this enzyme results in cells that require exogenous lipids and citrate to grow in hypoxia, inhibiting tumor growth and thus offering a novel strategy for the development of anti-cancer therapeutica.
This paper explores how metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis under pseudo-hypoxic conditions, regulated by HIF-1A, is a major factor in the development of rapidly proliferating tumours. Mapping of chromatin-binding sites has identified a novel facilitator of this metabolic shift, ARRB1, in prostate cancer, the most frequent cause of death in men in North America.
Prolyl hydroxylase domain proteins PHD’s act as oxygen sensors, regulating the stability of HIF as part of the hypoxia response and also targeting other metabolic and biosynthetic pathways that contribute to tumor growth. Yang et al. review the roles of PHD enzymes in cancer metabolism, including an extensive summary of PHD knockout mice and their phenotypes.
“Metabolism addiction in pancreatic cancer” Blum & Kloog, 2014
In this review, the concept of “metabolic addiction” is summarized and applied to the extremely fatal pancreatic cancers. Genomic aberrations accumulating during cancer cell proliferation dictate a dependency on abnormal signaling and metabolism pathways that are particularly potent in the hypoxic tumor microenvironment. Impacts of HIF, Ras and other signaling networks on autophagy, lipid and glutamine pathways, among others, are reviewed as targets for cancer therapy.