Nupr1-aurora kinase a pathway provides protection against metabolic stress-mediated autophagic-associated cell death

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

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)5234-5246
Number of pages13
JournalClinical Cancer Research
Volume18
Issue number19
DOIs
StatePublished - Oct 1 2012

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Aurora Kinases
Physiological Stress
Autophagy
Starvation
Aurora Kinase A
DNA Damage
Cell Death
RNA Interference
Gene Expression
Glucose
DNA Repair
Adenocarcinoma
cdc Genes
Survival
Microarray Analysis
Caspases
Heat-Shock Proteins
Pancreatic Neoplasms
Fluorescent Antibody Technique
Real-Time Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hamidi, T., Cano, C. E., Grasso, D., Garcia, M. N., Sandi, M. J., Calvo, E. L., ... Iovanna, J. L. (2012). Nupr1-aurora kinase a pathway provides protection against metabolic stress-mediated autophagic-associated cell death. Clinical Cancer Research, 18(19), 5234-5246. https://doi.org/10.1158/1078-0432.CCR-12-0026

Nupr1-aurora kinase a pathway provides protection against metabolic stress-mediated autophagic-associated cell death. / Hamidi, Tewfik; Cano, Carla E.; Grasso, Daniel; Garcia, Maria Noé; Sandi, Maria José; Calvo, Ezequiel L.; Dagorn, Jean Charles; Lomberk, Gwen; Urrutia, Raul; Goruppi, Sandro; Carracedo, Arkaitz; Velasco, Guillermo; Iovanna, Juan L.

In: Clinical Cancer Research, Vol. 18, No. 19, 01.10.2012, p. 5234-5246.

Research output: Contribution to journalArticle

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, JL 2012, 'Nupr1-aurora kinase a pathway provides protection against metabolic stress-mediated autophagic-associated cell death', Clinical Cancer Research, vol. 18, no. 19, pp. 5234-5246. https://doi.org/10.1158/1078-0432.CCR-12-0026
Hamidi, Tewfik ; Cano, Carla E. ; Grasso, Daniel ; Garcia, Maria Noé ; Sandi, Maria José ; Calvo, Ezequiel L. ; Dagorn, Jean Charles ; Lomberk, Gwen ; Urrutia, Raul ; Goruppi, Sandro ; Carracedo, Arkaitz ; Velasco, Guillermo ; Iovanna, Juan L. / Nupr1-aurora kinase a pathway provides protection against metabolic stress-mediated autophagic-associated cell death. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 19. pp. 5234-5246.
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AU - Hamidi, Tewfik

AU - Cano, Carla E.

AU - Grasso, Daniel

AU - Garcia, Maria Noé

AU - Sandi, Maria José

AU - Calvo, Ezequiel L.

AU - Dagorn, Jean Charles

AU - Lomberk, Gwen

AU - Urrutia, Raul

AU - Goruppi, Sandro

AU - Carracedo, Arkaitz

AU - Velasco, Guillermo

AU - Iovanna, Juan L.

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N2 - 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.

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