title: Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis.
abstract: Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic Kras(G12D), we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from Kras(G12D)-expressing pancreas. Moreover, pancreas-specific deletion of Relb in a Kras(G12D) background resulted in delayed in PanIN development associated with a lack of IER3 expression. Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients with PDAC, expression of NUPR1, RELB, and IER3 was significantly correlated with a poor prognosis. Cumulatively, these results reveal a NUPR1/RELB/IER3 stress-related pathway that is required for oncogenic Kras(G12D)-dependent transformation of the pancreas.
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM UMR 1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
authors.forename: Tewfik
authors.initials: T
authors.lastname: Hamidi
authors.forename: Hana
authors.initials: H
authors.lastname: Algül
authors.forename: Carla Eliana
authors.initials: CE
authors.lastname: Cano
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Sandi
authors.forename: Maria Inés
authors.initials: MI
authors.lastname: Molejon
authors.forename: Marc
authors.initials: M
authors.lastname: Riemann
authors.forename: Ezequiel Luis
authors.initials: EL
authors.lastname: Calvo
authors.forename: Gwen
authors.initials: G
authors.lastname: Lomberk
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Dagorn
authors.forename: Falk
authors.initials: F
authors.lastname: Weih
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.forename: Roland Michael
authors.initials: RM
authors.lastname: Schmid
authors.forename: Juan Lucio
authors.initials: JL
authors.lastname: Iovanna
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; C099815:IER3 protein, human; C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C491644:Nupr1 protein, mouse; C497593:RELB protein, human; C497594:Relb protein, mouse; D051841:Transcription Factor RelB; D015689:Oncogene Protein p21(ras)