Discovery of a novel glucose metabolism in cancer: The role of endoplasmic reticulum beyond glycolysis and pentose phosphate shunt

Cecilia Marini, Silvia Ravera, Ambra Buschiazzo, Giovanna Bianchi, Anna Maria Orengo, Silvia Bruno, Gianluca Bottoni, Laura Emionite, Fabio Pastorino, Elena Monteverde, Lucia Garaboldi, Roberto Martella, Barbara Salani, Davide Maggi, Mirco Ponzoni, Franco Fais, Lizzia Raffaghello, Gianmario Sambuceti

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Abstract

Cancer metabolism is characterized by an accelerated glycolytic rate facing reduced activity of oxidative phosphorylation. This "Warburg effect" represents a standard to diagnose and monitor tumor aggressiveness with (18)F-fluorodeoxyglucose whose uptake is currently regarded as an accurate index of total glucose consumption. Studying cancer metabolic response to respiratory chain inhibition by metformin, we repeatedly observed a reduction of tracer uptake facing a marked increase in glucose consumption. This puzzling discordance brought us to discover that (18)F-fluorodeoxyglucose preferentially accumulates within endoplasmic reticulum by exploiting the catalytic function of hexose-6-phosphate-dehydrogenase. Silencing enzyme expression and activity decreased both tracer uptake and glucose consumption, caused severe energy depletion and decreased NADPH content without altering mitochondrial function. These data document the existence of an unknown glucose metabolism triggered by hexose-6-phosphate-dehydrogenase within endoplasmic reticulum of cancer cells. Besides its basic relevance, this finding can improve clinical cancer diagnosis and might represent potential target for therapy.

Original languageEnglish
Pages (from-to)25092
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Apr 28 2016

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Marini, C., Ravera, S., Buschiazzo, A., Bianchi, G., Orengo, A. M., Bruno, S., Bottoni, G., Emionite, L., Pastorino, F., Monteverde, E., Garaboldi, L., Martella, R., Salani, B., Maggi, D., Ponzoni, M., Fais, F., Raffaghello, L., & Sambuceti, G. (2016). Discovery of a novel glucose metabolism in cancer: The role of endoplasmic reticulum beyond glycolysis and pentose phosphate shunt. Scientific Reports, 6, 25092. https://doi.org/10.1038/srep25092