Mandatory role of endoplasmic reticulum in preserving NADPH regeneration in starved MDA-MB-231 breast cancer cells

: 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.