Deciphering the metabolic basis and molecular circuitry of the Warburg effect in lymphoma

Abstract

Abstract Background: Prior to the widely recognized Krebs cycle, Otto Warburg observed aerobic glucose metabolism yielding lactate in malignant cells in 1923. Warburg's pioneering discovery made it possible to develop FDG-PET scans to diagnose cancer and develop LDH as a biomarker for hematological malignancies. Although lactate synthesis is a prominent metabolic feature of malignancy, its biological mechanisms, necessity, and significance remains unclear. Resolving the biological principles of the Warburg effect has revived interest in recent years due to recognition of metabolic reprogramming as a hallmark of cancer. However, most efforts have focused on upstream molecular features instead of directly resolving from a metabolic perspective. Methods: We developed a “metabolic overflow hypothesis" interlinking metabolic flux with cell cycle progression and explored metabolic behaviors in lymphoma. Through metabolic profiling of cell cycle phases, pharmacological perturbations and isotopic tracer studies comparing lymphoma and non-malignant lymphoblastoid cells, as well as validation of these metabolic profiles in human tumors, we provide insights into the molecular-metabolic circuitry underlying the Warburg effect. Results: Our results show that glucose carbons are diverted to nucleotide biosynthesis as the anabolic demand for nucleotides is higher in malignancy. Through pyruvate, glucose indirectly facilitates entry of glutamine carbons into TCA, thereby sustaining catabolism through TCA and energy metabolism. As a result of these metabolic actions, pyruvate is converted into alanine and lactate. Conclusion: Pyruvate is metabolically converted to lactate and alanine during S phase and is closely associated with the diversion of glucose for nucleotide synthesis, as well as maintaining the metabolic continuity of TCA through glutamine. Taken together, our study explains Warburg's metabolic paradox, i.e., the need for glucose and oxygen despite the reduction in glucose oxidation and the occurrence of pseudo-anaerobic lactate synthesis in cancer. Although these metabolic activities may appear to be part of physiological proliferation, their augmentation during malignancy results in increased metabolic supplies and nucleotides, which are necessary for oncogenic cell proliferation.