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

Abstract

It was already described that genetic inhibition of NUPR1 induces tumor growth arrest. In this paper we studied the metabolism changes after NUPR1 downregulation in pancreatic cancer cells, which results in a significant decrease of OXPHOS activity with a concomitant lower ATP production which precedes the necrotic cell death. We demonstrated that NUPR1 downregulation induces a mitochondrial failure with a loss of the mitochondrial membrane potential, a strong increase in ROS production and a concomitant relocalization of mitochondria to the vicinity of the endoplasmic reticulum (ER). In addition, the transcriptomic analysis of NUPR1-deficient cells shows a decrease in the expression of some ER stress response-associated genes. Indeed, in ER stressors-treated cells with thapsigargin, brefeldin A or tunicamycin, a greater increase in necrosis and decrease of ATP content was observed in NUPR1-defficent cells. Finally, in vivo experiments, using acute pancreatitis which induces ER stress as well as NUPR1 activation, we observed that NUPR1 expression protects acinar cells from necrosis in mice. Importantly, we also report that the cell death observed after knocking-down NUPR1 expression is completely reversed by incubation with Necrostatin-1, but not by inhibiting caspase activity with Z-VAD-FMK. 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 mediated by a programmed necrosis.

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

“…Taken together, these results strongly support a model in which, under ZZW-115 treatment, induced cell death is the con-and apoptosis. These results are in agreement with the fact that treating pancreatic cells with a siRNA against NUPR1 (33) or with TFP (our unpublished data) induces a similar metabolic disruption.…”

“…When OCR in MiaPaCa-2 cells was compared with untreated sequence of a decrease of ATP production by the mitochondria accompanied by an increase of mitochondrial ROS production with a transient metabolic shift toward anaerobic glycolysis. In agreement with our previous data, inhibition of apoptosis, and mainly necrosis by Nec-1 incubation, can restore metabolic functions and ATP content (33).…”

FANCD2 knockdown with shRNA interference enhances the ionizing radiation sensitivity of nasopharyngeal carcinoma CNE-2 cells

“…demonstrated that NUPR1 is involved in early breast cancer growth and mediates distant breast cancer metastasis [38]. Recent studies have reported that mitochondrial dysfunction in NUPR1-deficient pancreatic cancer cells leads to increased glycolysis, reduced ATP production, and an impaired cellular stress response, thereby promoting programmed cell death [39]. Zeng et al [40] found that knocking out NUPR1 inhibits the growth of U266 and RPMI8226 multiple myeloma cell lines via the activation of PTEN and caspase-dependent apoptosis.…”

Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry

“…The under expression of NUPR1 has been reported to result in increased ROS production thus creating a de cit in mitochondrial membrane potential. This alteration in OXPHOS activity has been associated with ER stress and triggers programmed necrosis in cancer cells [57]. During angiogenesis in cancer cells, NUPR1 was reported to be upregulated in association with triiodothyronine thyroid hormone receptor [58], which is regulated with TRH -Thyrotropin releasing hormone [59].…”