Oxygen availability and metabolic reprogramming in cancer

Abstract

Edited by Ruma BanerjeeHypoxia and dysregulated metabolism are defining features of solid tumors. How cancer cells adapt to low O 2 has been illuminated by numerous studies, with "reprogrammed" metabolism being one of the most important mechanisms. This metabolic reprogramming not only promotes cancer cell plasticity, but also provides novel insights for treatment strategies. As the most studied O 2 "sensor," hypoxia-inducible factor (HIF) is regarded as an important regulator of hypoxia-induced transcriptional responses. This minireview will summarize our current understanding of hypoxia-induced changes in cancer cell metabolism, with an initial focus on HIF-mediated effects, and will highlight how these metabolic alterations affect malignant phenotypes.Molecular oxygen (O 2 ) is a key nutrient required for aerobic metabolism to maintain intracellular bioenergetics and as a substrate in numerous organic and inorganic reactions. Hypoxia, defined by a deficiency in the amount of tissue O 2 levels, occurs in a variety of physiological as well as pathological conditions. Significant research interest in variable O 2 availability in cancers can be traced to the early 20th century, when Otto Warburg found that unlike most normal tissues, cancer cells preferentially "ferment" glucose to pyruvate and then lactate even in the presence of sufficient O 2 to support mitochondrial metabolism (the "Warburg effect"). Although the underlying mechanisms of this observation were not clear and numerous subsequent studies demonstrated certain limitations in this theory (especially the hypothesis that cancer cells develop a defect in mitochondria that leads to impaired aerobic respiration), it opened a new territory of investigating how cancer cells rewire metabolism to adapt to changes in O 2 levels. When facing hypoxia, cells modulate a number of conserved molecular responses, including those regulated by hypoxiainducible factors (HIFs), 3 endoplasmic reticulum (ER) stress responses, mechanistic target of rapamycin signaling, autophagy, and others. These processes promote altered metabolism to match O 2 supply. In this minireview, we will discuss hypoxia responses according to HIF-dependent and -independent pathways and how they impact progression of solid tumors. HIF-dependent metabolic reprogrammingThe HIF hydroxylase systemThe HIF system itself has been reviewed extensively elsewhere (1, 2). Initially identified as a transcriptional regulator bound to a hypoxia-response element (HRE) of the erythropoietin (EPO) gene to promote EPO production, it readily became apparent that this pathway operated much more widely, and it is currently recognized as a key modulator of the transcriptional response to hypoxic stress. Briefly, HIFs are heterodimeric transcription factors consisting of ␣ and ␤ subunits. Three HIF␣ isoforms exist in the mammalian genome (1␣, 2␣, and 3␣), of which HIF1␣ and HIF2␣ are the best characterized. HIF␣ subunits heterodimerize with stable HIF1␤ (or ARNT), recognize, and then bind to HREs ((G/A)CGTG) throughout...

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“…ROS production systems become elevated in more advanced stage cancer cells to promote their growth and survival . The tumor microenvironment during rapacious growth phases will concomitantly cause intermittent periods of hypoxia, acidosis, and nutrient deprivation resulting in hypoglycemia, all factors which consequently induce a major reprogramming of cancer cell metabolism . These microenvironmental stress related changes in cancer cell metabolism are frequently associated with greater ROS production …”