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

Patricia Santofimia-Castaño1, Wenjun Lan1, Jennifer Bintz1

  • 1Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.

Scientific Reports
|November 20, 2018
PubMed

Insights

Downregulating the NUPR1 gene in pancreatic cancer halts tumor growth by causing mitochondrial failure and programmed necrosis. This cell death is linked to endoplasmic reticulum stress and is reversible with Necrostatin-1.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Genetic inhibition of Nuclear Protein 1 (NUPR1) has been shown to arrest tumor growth.
  • Understanding metabolic shifts in pancreatic cancer following NUPR1 downregulation is crucial.

Purpose of the Study:

  • To investigate the metabolic consequences of NUPR1 downregulation in pancreatic cancer cells.
  • To elucidate the role of NUPR1 in mitochondrial function, endoplasmic reticulum (ER) stress, and cell death pathways.

Main Methods:

  • Studied metabolic changes, including OXPHOS activity and ATP production, after NUPR1 downregulation.
  • Assessed mitochondrial function (membrane potential, ROS production) and organelle localization.
  • Performed transcriptomic analysis and treated cells with ER stressors (thapsigargin, brefeldin A, tunicamycin).
  • Conducted in vivo experiments using a mouse model of acute pancreatitis and utilized Necrostatin-1 and Z-VAD-FMK for cell death inhibition.

Main Results:

  • NUPR1 downregulation significantly decreased OXPHOS activity and ATP production, preceding necrotic cell death.
  • Mitochondrial failure, loss of membrane potential, increased ROS, and ER relocalization were observed.
  • NUPR1 deficiency exacerbated necrosis and ATP reduction under ER stress conditions.
  • NUPR1 expression protected pancreatic acinar cells from necrosis in an acute pancreatitis model.
  • Cell death induced by NUPR1 knockdown was reversed by Necrostatin-1, indicating programmed necrosis, but not by caspase inhibition.

Conclusions:

  • NUPR1 inactivation in pancreatic cancer triggers ER stress, leading to mitochondrial dysfunction, reduced ATP, and programmed necrosis.
  • NUPR1 plays a protective role against necrosis in pancreatic acinar cells during ER stress.
  • The findings establish a model linking NUPR1, ER stress, mitochondrial failure, and programmed necrosis in pancreatic cancer.

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