Abstract
BackgroundCancer cells exhibit increased glycolysis for ATP production (the Warburg effect) and macromolecular biosynthesis; it is also linked with therapeutic resistance that is generally associated with compromised respiratory metabolism. Molecular mechanisms underlying radio-resistance linked to elevated glycolysis remain incompletely understood.MethodsWe stimulated glycolysis using mitochondrial respiratory modifiers (MRMs viz. di-nitro phenol, DNP; Photosan-3, PS3; Methylene blue, MB) in established human cell lines (HEK293, BMG-1 and OCT-1). Glucose utilization and lactate production, levels of glucose transporters and glycolytic enzymes were investigated as indices of glycolysis. Clonogenic survival, DNA repair and cytogenetic damage were studied as parameters of radiation response.ResultsMRMs induced the glycolysis by enhancing the levels of two important regulators of glucose metabolism GLUT-1 and HK-II and resulted in 2 fold increase in glucose consumption and lactate production. This increase in glycolysis resulted in resistance against radiation-induced cell death (clonogenic survival) in different cell lines at an absorbed dose of 5 Gy. Inhibition of glucose uptake and glycolysis (using fasentin, 2-deoxy-D-glucose and 3-bromopyruvate) in DNP treated cells failed to increase the clonogenic survival of irradiated cells, suggesting that radio-resistance linked to inhibition of mitochondrial respiration is glycolysis dependent. Elevated glycolysis also facilitated rejoining of radiation-induced DNA strand breaks by activating both non-homologous end joining (NHEJ) and homologous recombination (HR) pathways of DNA double strand break repair leading to a reduction in radiation-induced cytogenetic damage (micronuclei formation) in these cells.ConclusionsThese findings suggest that enhanced glycolysis generally observed in cancer cells may be responsible for the radio-resistance, partly by enhancing the repair of DNA damage.
Highlights
Cancer cells exhibit increased glycolysis for ATP production and macromolecular biosynthesis; it is linked with therapeutic resistance that is generally associated with compromised respiratory metabolism
At Treatment of exponentially growing cells with non-toxic concentrations mitochondrial respiratory modifiers (MRMs) such as di-nitrophenol (DNP), porphyrin derivatives and methylene blue (MB), which interfere with the oxidative phosphorylation at different stages in the electron transport chain (ETC), was found to enhance the glycolysis significantly in both malignant cell lines BMG-1 and OCT-1 (Figure 1A and B), similar to our earlier results with KCN [11,12]
To test if compromised oxidative phosphorylation can induce the compensatory increase in glycolysis in non-malignant cell similar to malignant cells, we treated HEK cell line with MRMs under similar experimental conditions
Summary
Cancer cells exhibit increased glycolysis for ATP production (the Warburg effect) and macromolecular biosynthesis; it is linked with therapeutic resistance that is generally associated with compromised respiratory metabolism. Molecular mechanisms underlying radio-resistance linked to elevated glycolysis remain incompletely understood. The molecular mechanisms underlying this radio-resistance of cancer cells remain poorly understood. Cells derived from hypoxic tumors typically maintain their metabolic phenotypes even under normoxic culture conditions (Warburg effect), indicating that aerobic glycolysis is constitutively upregulated through stable genetic or epigenetic changes [2]. It is reported that mitochondrial defect linked stabilization of HIF1α induces glycolytic phenotype in cancer cells and promotes aggressiveness of tumors [2,3]. Metabolically reprogrammed and highly glycolytic cancer cells can escape the death processes, conferring resistance to therapeutic modalities [5]
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