The contribution of the reticular Pentose Phosphate Pathway in glucose metabolism, cell proliferation and in the regulation of the redox state

The use of Positron Emission Tomography (PET)/ Computed tomography (CT) with 18F-2-deoxy-glucose (FDG) represents a clinical standard for the diagnosis and monitoring of cancer evolution and in the evaluation of many neurodegenerative syndromes. This method relies on the concept that FDG competes with glucose for trans-membrane transport (GLUTs) and hexokinase (HK)-catalyzed phosphorylation (1). However, FDG-6-phosphate (FDG6P) is a false substrate for downstream enzymes channeling glucose-6P (G6P) to glycolysis, pentose phosphate pathway (PPP) or glycogen synthesis (2-3) and thus accumulates within the cytosol as a function of glucose consumption. Despite the universal acceptance of this kinetic model, the link between glucose consumption and FDG uptake might be relatively looser than conventionally assumed. Indeed, glucose consumption is invariably high also in those cancers (prostate, urothelial and neuroendocrine cancers or glioblastoma) characterized by a very low FDG uptake (4-6). Finally, the theoretical nondegradability of 2DG6P/FDG6P has been recently challenged by two main observations: on the one hand, stoichiometry indicates that a significant fraction of intracellular 2DG is not processed by HKs (7); on the other hand, magnetic resonance spectroscopy documents significant degradation of FDG6 (8-10). To date, the relationship between FDG uptake and glucose consumption is almost universally accepted. Nevertheless, several observations indicate that the link between glucose consumption and FDG accumulation may be relatively looser than conventionally assumed. In agreement with this concept, recent studies recently documented cancer uptake of FDG is closely and selectively dependent on a specific metabolism triggered within the endoplasmic reticulum (ER) by the enzyme hexose-6- phosphate dehydrogenase (H6PD) whose silencing profoundly diminished FDG uptake despite an increase in glycolytic flux (11). This autosomic counterpart of the cytosolic glucose-6-phosphate-dehydrogenase (G6PD) can dehydrogenate many hexoses, including 2-deoxy-glucose (2DG), to trigger pentose-phosphate pathway (PPP) and thus to fuel the high NADPH within the ER lumen (12-14). My project aimed to study the role of H6PD in FDG uptake or, more in general, to evaluate the contribution of the ER-PPP in global cell glucose metabolism, proliferation, and regulation of the redox state. Obtained results indicate that FDG uptake is indeed strictly dependent upon the activation of ER metabolic machinery and only loosely related to glycolytic flux. More importantly, they also suggest an unexpected relevance of ER glucose metabolism in feeding the high NADPH equivalents required by cells with high proliferating activity or exposed to an intense redox stress.