Mandatory role of endoplasmic reticulum in preserving NADPH regeneration in starved MDA-MB-231 breast cancer cells
Sonia Carta,
Vanessa Cossu,
Francesca Vitale,
Matteo Bauckneht,
Maddalena Ghelardoni,
Anna Maria Orengo,
Serena Losacco,
Daniela Gaglio,
Silvia Bruno,
Sabrina Chiesa,
Silvia Ravera,
Gianmario Sambuceti,
Cecilia Marini
Affiliations
Sonia Carta
IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy; Corresponding author.
Vanessa Cossu
Department of Experimental Medicine, Human Anatomy Section, University of Genoa, 16132, Genova, Italy
Francesca Vitale
IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
Matteo Bauckneht
IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy; Department of Health Sciences, University of Genoa, 16132, Genova, Italy
Maddalena Ghelardoni
IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
Anna Maria Orengo
IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
Serena Losacco
IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
Daniela Gaglio
Institute of Molecular Bioimaging and Complex Biological Systems (IBSBC-CNR), National Research Council (CNR), 20054, Milan, Italy
Silvia Bruno
Department of Experimental Medicine, Human Anatomy Section, University of Genoa, 16132, Genova, Italy
Sabrina Chiesa
IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
Silvia Ravera
Department of Experimental Medicine, Human Anatomy Section, University of Genoa, 16132, Genova, Italy
Gianmario Sambuceti
IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy; Department of Health Sciences, University of Genoa, 16132, Genova, Italy
Cecilia Marini
IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy; Institute of Molecular Bioimaging and Complex Biological Systems (IBSBC-CNR), National Research Council (CNR), 20054, Milan, Italy
Cancer growth requires high amount of nicotinamide adenine dinucleotide phosphate (NADPH) to feed the anabolic reactions and preserve the redox balance. NADPH level is largely preserved by the oxidative arm of the pentose phosphate pathway (PPP). Here, we show that prolonged glucose deprivation of triple negative breast cancer MDA-MB-231 cells decreases proliferation rate, promotes hexose funneling to glycolysis hampering the PPP. The impairment in PPP activity and the consequent NADPH depletion are partially counterbalanced by enhancing the malic enzyme-1 catalyzed conversion of glutamine-derived malate to pyruvate. However, the use of these glucose-independent carbons implies the integrity of the two PPPs represented in all eukaryotic cells, i.e., the well-recognized cytosolic PPP, triggered by glucose-6-phosphate dehydrogenase (G6PD) and its reticular counterpart, triggered by hexose-6P-dehydrogenase (H6PD). This evidence configures the reticular PPP as a mandatory player in the regeneration of NADPH reductive power by cancer cells.
