The Warburg effect: a balance of flux analysis

Abstract

Cancer metabolism is characterized by increased macromolecular syntheses through coordinated increases in energy and substrate metabolism. The observation that cancer cells produce lactate in an environment of oxygen sufficiency (aerobic glycolysis) is a central theme of cancer metabolism known as the Warburg effect. Aerobic glycolysis in cancer metabolism is accompanied by increased pentose cycle and anaplerotic activities producing energy and substrates for macromolecular synthesis. How these processes are coordinated is poorly understood. Recent advances have focused on molecular regulation of cancer metabolism by oncogenes and tumor suppressor genes which regulate numerous enzymatic steps of central glucose metabolism. In the past decade, new insights in cancer metabolism have emerged through the application of stable isotopes particularly from 13C carbon tracing. Such studies have provided new evidence for system-wide changes in cancer metabolism in response to chemotherapy. Interestingly, experiments using metabolic inhibitors on individual biochemical pathways all demonstrate similar system-wide effects on cancer metabolism as in targeted therapies. Since biochemical reactions in the Warburg effect place competing demands on available precursors, high energy phosphates and reducing equivalents, the cancer metabolic system must fulfill the condition of balance of flux (homeostasis). In this review, the functions of the pentose cycle and of the tricarboxylic acid (TCA) cycle in cancer metabolism are analyzed from the balance of flux point of view. Anticancer treatments that target molecular signaling pathways or inhibit metabolism alter the invasive or proliferative behavior of the cancer cells by their effects on the balance of flux (homeostasis) of the cancer metabolic phenotype.

Proliferation of sphere-forming hepatocellular carcinoma cells is suppressed in a medium without glucose and arginine, but with galactose and ornithine

“…Cancer cells require more glucose than normal cells due to the Warburg effect (11). Therefore, glucose metabolism is a potential therapeutic target for the treatment of HCC.…”

“…Cancer cells have increased glycolysis levels, requiring more glucose under insufficient oxygen supply (Warburg effect), compared with surrounding normal tissues (11). Glucose is essential for cell survival (12,13).…”

Comparison of DWIBS/T2 image fusion and PET/CT for the diagnosis of cancer in the abdominal cavity

“…In order to improve the prognosis of these diseases, early detection of pancreatic cancer is important (7). 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) takes advantage of the Warburg effect (8), which suggests that cancer cells require more glucose than normal cells due to the activation of glycolysis. Therefore, cancer cells readily take up 18 F-FDG, an analogue of glucose, which is then not metabolized and accumulates inside these cells to a much greater extent than in non-cancerous cells.…”

Proliferation and motility of hepatocellular, pancreatic and gastric cancer cells grown in a medium without glucose and arginine, but with galactose and ornithine

“…Metabolism in cancer cells is characterized by increased aerobic glycolysis and lactate production, even under a sufficient oxygen supply (the Warburg effect), and cancer cells require more glucose compared with the surrounding normal tissues (9). This phenomenon is applied to positron emission tomography, in which 18-fluorodeoxyglucose, an analogue of glucose, is taken up by cancer cells (10).…”