Nupr1-Aurora Kinase A Pathway Provides Protection against Metabolic Stress-Mediated Autophagic-Associated Cell Death

Abstract

Purpose: The limited supply of oxygen and nutrients is thought to result in rigorous selection of cells that will eventually form the tumor.Experimental Design: Nupr1 expression pattern was analyzed in human tissue microarray (TMA) and correlated with survival time of the patient. Microarray analysis was conducted on MiaPaCa2 cells subjected to metabolic stress in Nupr1-silenced conditions. DNA repair and cell cycle-associated gene expression was confirmed by real-time quantitative PCR (qRT-PCR). Nupr1 and AURKA protective role were analyzed using RNA interference (RNAi) silencing or overexpression. DNA damage and autophagy were analyzed by Western blot analysis and immunofluorescence.Results: We showed that both Nupr1 and HIF1a are coexpressed in human pancreatic ductal adenocarcinoma (PDAC) samples and negatively correlate with survival time. PDAC-derived cells submitted to hypoxia and/or glucose starvation induce DNA damage-dependent cell death concomitantly to the overexpression of stress protein Nupr1. Affymetrix-based transcriptoma analysis reveals that Nupr1 knockdown enhances DNA damage and alters the expression of several genes involved in DNA repair and cell-cycle progression. Expression of some of these genes is common to hypoxia and glucose starvation, such as Aurka gene, suggesting that Nupr1 overexpression counteracts the transcriptional changes occurring under metabolic stress. The molecular mechanism by which hypoxia and glucose starvation induce cell death involves autophagy-associated, but not caspase-dependent, cell death. Finally, we have found that AURKA expression is partially regulated by Nupr1 and plays a major role in this response.Conclusions: Our data reveal that Nupr1 is involved in a defense mechanism that promotes pancreatic cancer cell survival when exposed to metabolic stress.

Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets

“…Profiling small intestinal neuroendocrine tumors mesenchymal transition and metastasis, 30,31 was activated in a subset of tumors (cluster B), which was associated with shorter patient survival. We also found nuclear protein 1 (NUPR1), a chromatin binding protein regulating stress response and resistance to chemotherapy, 32 to be activated in another subset of tumors (cluster C). Significantly deregulated pathways in tumor clusters may indicate molecular mechanism involved in the formation of these tumors.…”

Nidogen 1 and Nuclear Protein 1: novel targets of ETV5 transcription factor involved in endometrial cancer invasion

“…Overexpression of NUPR1 in the invasion front may be related to other roles of NUPR1 in cell invasion such as tumor survival. NUPR1 has been shown to protect cells from stress-induced death by inhibiting apoptosis [24]. NUPR1 has been found to be overexpressed and to play a role in pancreatic, pituitary, breast and thyroid cancer [25].…”

CpG Preconditioning Regulates Mirna Expression That Modulates Genomic Reprogramming Associated with Neuroprotection against Ischemic Injury

“…Finally, Nupr1, which is most studied in pancreatic cancer, promotes survival of cancerous cells in the face of severe environmental conditions, such as hypoxia, by making the cell resistant to metabolic stress that causes autophagymediated cell death. 20,21 To our knowledge, this is the first account of Nupr1 upregulation in the brain after stroke. We postulate that Nupr1 expression may increase cell survival by increasing resistance to metabolic stress induced by cerebral ischemia.…”

“…cellular stress. 20,21 Nkx2-2 has neuroprotective potential as it may be involved in restorative processes through adult myelination and oligodendrocyte maturation. 22 Finally, Mthfd2 is part of the folate pathway, and folic acid is known to be neuroprotective against stroke.…”