Inactivation of NUPR1 promotes cell death by coupling ER-stress responses with necrosis

Abstract

Genetic inhibition of NUPR1 induces tumor growth arrest. Inactivation of NUPR1 expression in pancreatic cancer cells results in lower ATP production, higher consumption of glucose with a significant switch from OXPHOS to glycolysis followed by necrotic cell death. Importantly, induction of necrosis is independent of the caspase activity. We demonstrated that NUPR1 inactivation triggers a massive release of Ca2+ from the endoplasmic reticulum (ER) to the cytosol and a strong increase in ROS production by mitochondria with a concomitant relocalization of mitochondria to the vicinity of the ER. In addition, transcriptomic analysis of NUPR1-deficient cells shows the induction of an ER stress which is associated to a decrease in the expression of some ER stress response-associated genes. Indeed, during ER stress induced by the treatment with thapsigargin, brefeldin A or tunicamycin, an increase in the mitochondrial malfunction with higher induction of necrosis was observed in NUPR1-defficent cells. Finally, activation of NUPR1 during acute pancreatitis protects acinar cells of necrosis in mice. Altogether, these data enable us to describe a model in which inactivation of NUPR1 in pancreatic cancer cells results in an ER stress that induces a mitochondrial malfunction, a deficient ATP production and, as consequence, the cell death by necrosis.\n\nHighlightsNUPR1 expression promotes pancreatic cancer development and progression\n\nNUPR1-depletion is a promising therapeutic strategy to be used for treating cancers\n\nNUPR1-depletion induces ER stress, mitochondrial malfunction and a significant switch from OXPHOS to glycolysis followed by necrotic cell death\n\nInactivation of NUPR1 antagonizes cell growth by coupling a defective ER-stress response and a caspase-independent necrosis.