Energy metabolism in human melanoma cells under hypoxic and acidic conditions in vitro

Abstract

Summary The response to treatment and the malignant progression of tumours are influenced by the ability of the tumour cells to withstand severe energy deprivation during prolonged exposure to hypoxia at normal or low extracellular pH (pHe). The objective of the present work was to demonstrate intertumour heterogeneity under conditions of microenvironment-induced energy deprivation and to investigate whether the heterogeneity can be attributed to differences in the capacity of the tumour cells to generate energy in an oxygen-deficient microenvironment. Cultures of four human melanoma cell lines (BEX-c, COX-c, SAX-c, WIX-c) were exposed to hypoxia in vitro at PHe 7.4, 7.0 or 6.6 for times up to 31 h by using the steel-chamber method. High-performance liquid chromatography was used to assess adenylate energy charge as a function of exposure time. Cellular rates of glucose uptake and lactate release were determined by using standard enzymatic test kits. The adenylate energy charge decreased with time under hypoxia in all cell lines. The decrease was most pronounced shortly after the treatment had been initiated and then tapered off. BEX-c and SAX-c showed a significantly higher adenylate energy charge under hypoxic conditions than did COX-c and WIX-c whether the PHe was 7.4, 7.0 or 6.6, showing that tumours can differ in the ability to avoid energy deprivation during microenvironmental stress. There was no correlation between the adenylate energy charge and the rates of glucose uptake and lactate release. Intertumour heterogeneity in the ability to withstand energy deprivation in an oxygen-deficient microenvironment cannot therefore be attributed mainly to differences in the capacity of the tumour cells to generate energy by anaerobic metabolism. The data presented here suggest that the heterogeneity is rather caused by differences in the capacity of the tumour cells to reduce the rate of energy consumption when exposed to hypoxia.

Effects of tumour acidification with glucose+MIBG on the spontaneous metastatic potential of two murine cell lines

“…Despite previously demonstrated cyclical reduction in tumour pO 2 during acute hypoxia and evidence for enhanced glycolysis rates following hypoxic culture conditions (Skoyum et al, 1997;Cairns et al, 2001), acute hypoxia resulted in a small reduction in pH e only in the B16F1 model. The mean change from the untreated control values was þ 0.10 pH units for the KHT-C (range: from À0.15 to þ 0.41 pH units) and À0.13 pH units for the B16F1 tumours (range: from À0.26 to þ 0.14 pH units; Figure 1).…”

Genotoxicity and Cytotoxicity of novel 10B carrier ((2R)-4,5,6-trihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)boronic acid

“…An increase in the tumor tissue biomass also increases the energy needs and decreases the oxygen supplies. Consequently, the required ATP is produced through anaerobic pathways [11]. The yield of the anaerobic synthesis of ATP is very low and leads to an increased glucose consumption rate [43].…”

“…In addition to depleting energy in cells, 2-DG has also been found to alter N-linked glycosylation, which results in unfolded protein responses and the induction of changes in the gene expression and phosphorylation status of proteins involved in signalling, cell cycle control, DNA repair, calcium influx, and apoptosis [10]. It is well known that the glucose metabolism in tumor tissue increases due to, for example, the lack of oxygen, a decreased oxidative phosphorylation, the activation of anaerobic respiration pathway by tumorogenic cells for ATP synthesis, and finally the requirement of excess glucose consumption [11]. Due to the affinity of glucose to tumor tissue, 18 F conjugated glucose ( 18 F-Deoxy-D-glucose) is routinely used for the detection and staging of tumors with positron emission tomography (PET).…”

Review: Implications of In Vitro Research on the Effect of Radiotherapy and Chemotherapy Under Hypoxic Conditions

“…Skoyum et al [74] suggested that hypoxic tumor cells differ in their ability to avoid severe energy deprivation. These differences would be mainly attributable to differences in the capacity of cells to reduce energy-requiring processes rather than to differences in the capacity to generate energy by anaerobic glycolysis.…”