De Novo Diacylglycerol Synthesis from Glucose: A Forgotten Link Between the Warburg Effect, Endogenous Tumor Promotion, and Ras-Driven Carcinogenesis

The Warburg effect – aerobic glycolysis with massive glucose consumption and lactate production – is a hallmark of cancer. In 1989 we demonstrated in EJ-H-ras-transformed BALB/3T3 fibroblasts that glucose is not merely a fuel but the substrate for de novo synthesis of 1,2-diacylglycerol (DAG) via the glycolytic intermediates dihydroxyacetone phosphate and glycerol-3-phosphate. This glucose-derived DAG, rich in saturated fatty acids (palmitate), accumulates constitutively, activates protein kinase C (PKC), and subverts agonist-stimulated inositol lipid metabolism. Because PKC is the intracellular receptor for phorbol esters (classic tumor promoters), ras-transformed cells autonomously generate both the initiating oncogene (ras) and the promoting signal (endogenous DAG/PKC). This creates a complete, self-sustaining multistage carcinogenesis loop inside a single cell. The observation, cited only ~20–46 times in 36 years, explains why sugar is “much worse” than a simple energy source: it supplies the raw material for an oncometabolite that mimics phorbol esters. Modern knowledge on lipid reprogramming, PKC isoforms in ras-driven cancers, and ketogenic-diet trials validates this 1989 mechanism and calls for its resurrection as a therapeutic target.