International Journal of
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Mini Review Volume 13 Issue 4
De novo diacylglycerol synthesis from glucose: a forgotten link between the warburg effect, endogenous tumor promotion, and RAS-driven carcinogenesis. Implications for radiation therapy of cancer
Marco Ruggiero
Received: July 31, 2026 | Published: August 18, 2026
Citation: Ruggiero M. De novo diacylglycerol synthesis from glucose: a forgotten link between the warburg effect, endogenous tumor promotion, and RASdriven carcinogenesis. Implications for radiation therapy of cancer. Int J Radiol Radiat Ther. 2026;13(4):85-87. DOI: 10.15406/ijrrt.2026.13.00460
Abstract
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 few times in 37 years, suggests that, in this specific experimental context, glucose can serve not only as an energy source but also as a substrate for the generation of an endogenous, phorbol-ester-like promoter. 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. These findings carry direct implications for oncological radiotherapy, as constitutive glucose-derived DAG/PKC signaling may contribute to radioresistance in RAS-driven tumors (supported by evidence linking DAG/PKC to ionizing radiation responses, ROS and survival signaling) and therefore represents a rational target for radiosensitizing strategies.
Keywords: warburg effect, protein kinase c, endogenous tumor promotion, RAS oncogene, glucose metabolism, ketogenic diet, radiation therapy
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