Discovery of a novel glucose metabolism in cancer: The role of endoplasmic reticulum beyond glycolysis and pentose phosphate shunt.
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.
CNR Institute of Molecular Bioimaging and Physiology (IBFM), Milan, Section of Genoa, Genoa, Italy.|Nuclear Medicine Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
Cecilia
C
Marini
Stem Cell Center, IRCCS G. Gaslini, Genoa, Italy.
Silvia
S
Ravera
Nuclear Medicine Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
Ambra
A
Buschiazzo
Laboratorio di Oncologia, IRCCS G. Gaslini, Genoa, Italy.
Giovanna
G
Bianchi
Nuclear Medicine Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
Anna Maria
AM
Orengo
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Silvia
S
Bruno
Nuclear Medicine Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
Gianluca
G
Bottoni
Animal facility, IRCCS AOU San Martino-IST, Genoa, Italy.
Laura
L
Emionite
Laboratorio di Oncologia, IRCCS G. Gaslini, Genoa, Italy.
Fabio
F
Pastorino
Nuclear Medicine Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
Elena
E
Monteverde
Nuclear Medicine Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
Lucia
L
Garaboldi
Laboratorio di Oncologia, IRCCS G. Gaslini, Genoa, Italy.
Roberto
R
Martella
Department of Internal Medicine, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
Barbara
B
Salani
Department of Internal Medicine, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
Davide
D
Maggi
Laboratorio di Oncologia, IRCCS G. Gaslini, Genoa, Italy.
Mirco
M
Ponzoni
Department of Experimental Medicine, University of Genoa, Genoa, Italy.|Molecular Pathology, IRCCS AOU San Martino-IST, Genoa, Italy.
Franco
F
Fais
Laboratorio di Oncologia, IRCCS G. Gaslini, Genoa, Italy.
Lizzia
L
Raffaghello
Nuclear Medicine Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
Gianmario
G
Sambuceti
D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000503:physiopathology*; D010427:Pentose Phosphate Pathway
D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D005947:Glucose