Nupr1-aurora kinase A pathway provides protection against metabolic stress-mediated autophagic-associated cell death. Clin Cancer Res 2012 Oct 01;18(19):5234-46
Date
08/18/2012Pubmed ID
22899799DOI
10.1158/1078-0432.CCR-12-0026Scopus ID
2-s2.0-84866931110 (requires institutional sign-in at Scopus site) 60 CitationsAbstract
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 HIF1α 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.
Author List
Hamidi T, Cano CE, Grasso D, Garcia MN, Sandi MJ, Calvo EL, Dagorn JC, Lomberk G, Urrutia R, Goruppi S, Carracedo A, Velasco G, Iovanna JLAuthors
Gwen Lomberk PhD Professor in the Surgery department at Medical College of WisconsinRaul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdenocarcinomaAurora Kinase A
Aurora Kinases
Autophagy
Basic Helix-Loop-Helix Transcription Factors
Carcinoma, Pancreatic Ductal
Cell Hypoxia
Cell Line, Tumor
Cell Survival
Gene Expression Regulation, Neoplastic
Glucose
Humans
Neoplasm Proteins
RNA Interference
Stress, Physiological
