Document Detail


Nupr1-aurora kinase A pathway provides protection against metabolic stress-mediated autophagic-associated cell death.
MedLine Citation:
PMID:  22899799     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Tewfik Hamidi; Carla E Cano; Daniel Grasso; Maria Noé Garcia; Maria José Sandi; Ezequiel L Calvo; Jean-Charles Dagorn; Gwen Lomberk; Raul Urrutia; Sandro Goruppi; Arkaitz Carracedo; Guillermo Velasco; Juan L Iovanna
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-16
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  18     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-02     Completed Date:  2013-05-03     Revised Date:  2014-04-08    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5234-46     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma* / metabolism,  pathology
Aurora Kinase A
Aurora Kinases
Autophagy
Basic Helix-Loop-Helix Transcription Factors* / genetics,  metabolism
Carcinoma, Pancreatic Ductal* / metabolism,  pathology
Cell Hypoxia
Cell Line, Tumor
Cell Survival
Gene Expression Regulation, Neoplastic
Glucose / metabolism
Humans
Neoplasm Proteins* / genetics,  metabolism
Protein-Serine-Threonine Kinases* / genetics,  metabolism
RNA Interference
Stress, Physiological
Chemical
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/Neoplasm Proteins; 0/P8 protein, human; EC 2.7.11.1/AURKA protein, human; EC 2.7.11.1/Aurora Kinase A; EC 2.7.11.1/Aurora Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; IY9XDZ35W2/Glucose

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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