HDM2 regulation by AURKA promotes cell survival in gastric cancer

Vikas Sehdev, Ahmed Katsha, Janet Arras, Dunfa Peng, Mohammed Soutto, Jeffrey Ecsedy, Alexander Zaika, Abbes Belkhiri, Wael El-Rifai

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Purpose: Suppression of P53 (tumor protein 53) transcriptional function mediates poor therapeutic response in patients with cancer. Aurora kinase A (AURKA) and human double minute 2 (HDM2) are negative regulators of P53. Herein, we examined the role of AURKA in regulating HDM2 and its subsequent effects on P53 apoptotic function in gastric cancer. Experimental Design: Primary tumors and in vitro gastric cancer cell models with overexpression or knockdown of AURKA were used. The role of AURKA in regulating HDM2 and cell survival coupled with P53 expression and activity were investigated. Results: Overexpression of AURKA enhanced the HDM2 protein level; conversely, knockdown of endogenous AURKA decreased expression of HDM2 in AGS and SNU-1 cells. Dual co- immunoprecipitation assay data indicated that AURKA was associated with HDM2 in a protein complex. The in vitro kinase assay using recombinant AURKA and HDM2 proteins followed by co-immunoprecipitation revealed that AURKA directly interacts and phosphorylates HDM2 protein in vitro. The activation of HDM2 by AURKA led to induction of P53 ubiquitination and attenuation of cisplatin-induced activation of P53 in gastric cancer cells. Inhibition of AURKA using an investigational small-molecule specific inhibitor, alisertib, decreased the HDM2 protein level and induced P53 transcriptional activity. These effects markedly decreased cell survival in vitro and xenograft tumor growth in vivo. Notably, analysis of immunohistochemistry on tissue microarrays revealed significant overexpression of AURKA and HDM2 in human gastric cancer samples (P < 0.05). Conclusion: Collectively, our novel findings indicate that AURKA promotes tumor growth and cell survival through regulation of HDM2-induced ubiquitination and inhibition of P53. Clin Cancer Res; 20(1); 76-86.

Original languageEnglish (US)
Pages (from-to)76-86
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Aurora Kinase A
Stomach Neoplasms
Cell Survival
Neoplasms
Proteins
Ubiquitination
Immunoprecipitation
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

HDM2 regulation by AURKA promotes cell survival in gastric cancer. / Sehdev, Vikas; Katsha, Ahmed; Arras, Janet; Peng, Dunfa; Soutto, Mohammed; Ecsedy, Jeffrey; Zaika, Alexander; Belkhiri, Abbes; El-Rifai, Wael.

In: Clinical Cancer Research, Vol. 20, No. 1, 01.01.2014, p. 76-86.

Research output: Contribution to journalArticle

Sehdev, Vikas ; Katsha, Ahmed ; Arras, Janet ; Peng, Dunfa ; Soutto, Mohammed ; Ecsedy, Jeffrey ; Zaika, Alexander ; Belkhiri, Abbes ; El-Rifai, Wael. / HDM2 regulation by AURKA promotes cell survival in gastric cancer. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 1. pp. 76-86.
@article{55fbbbd294f24fa7831ca92e37be0eed,
title = "HDM2 regulation by AURKA promotes cell survival in gastric cancer",
abstract = "Purpose: Suppression of P53 (tumor protein 53) transcriptional function mediates poor therapeutic response in patients with cancer. Aurora kinase A (AURKA) and human double minute 2 (HDM2) are negative regulators of P53. Herein, we examined the role of AURKA in regulating HDM2 and its subsequent effects on P53 apoptotic function in gastric cancer. Experimental Design: Primary tumors and in vitro gastric cancer cell models with overexpression or knockdown of AURKA were used. The role of AURKA in regulating HDM2 and cell survival coupled with P53 expression and activity were investigated. Results: Overexpression of AURKA enhanced the HDM2 protein level; conversely, knockdown of endogenous AURKA decreased expression of HDM2 in AGS and SNU-1 cells. Dual co- immunoprecipitation assay data indicated that AURKA was associated with HDM2 in a protein complex. The in vitro kinase assay using recombinant AURKA and HDM2 proteins followed by co-immunoprecipitation revealed that AURKA directly interacts and phosphorylates HDM2 protein in vitro. The activation of HDM2 by AURKA led to induction of P53 ubiquitination and attenuation of cisplatin-induced activation of P53 in gastric cancer cells. Inhibition of AURKA using an investigational small-molecule specific inhibitor, alisertib, decreased the HDM2 protein level and induced P53 transcriptional activity. These effects markedly decreased cell survival in vitro and xenograft tumor growth in vivo. Notably, analysis of immunohistochemistry on tissue microarrays revealed significant overexpression of AURKA and HDM2 in human gastric cancer samples (P < 0.05). Conclusion: Collectively, our novel findings indicate that AURKA promotes tumor growth and cell survival through regulation of HDM2-induced ubiquitination and inhibition of P53. Clin Cancer Res; 20(1); 76-86.",
author = "Vikas Sehdev and Ahmed Katsha and Janet Arras and Dunfa Peng and Mohammed Soutto and Jeffrey Ecsedy and Alexander Zaika and Abbes Belkhiri and Wael El-Rifai",
year = "2014",
month = "1",
day = "1",
doi = "10.1158/1078-0432.CCR-13-1187",
language = "English (US)",
volume = "20",
pages = "76--86",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - HDM2 regulation by AURKA promotes cell survival in gastric cancer

AU - Sehdev, Vikas

AU - Katsha, Ahmed

AU - Arras, Janet

AU - Peng, Dunfa

AU - Soutto, Mohammed

AU - Ecsedy, Jeffrey

AU - Zaika, Alexander

AU - Belkhiri, Abbes

AU - El-Rifai, Wael

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Purpose: Suppression of P53 (tumor protein 53) transcriptional function mediates poor therapeutic response in patients with cancer. Aurora kinase A (AURKA) and human double minute 2 (HDM2) are negative regulators of P53. Herein, we examined the role of AURKA in regulating HDM2 and its subsequent effects on P53 apoptotic function in gastric cancer. Experimental Design: Primary tumors and in vitro gastric cancer cell models with overexpression or knockdown of AURKA were used. The role of AURKA in regulating HDM2 and cell survival coupled with P53 expression and activity were investigated. Results: Overexpression of AURKA enhanced the HDM2 protein level; conversely, knockdown of endogenous AURKA decreased expression of HDM2 in AGS and SNU-1 cells. Dual co- immunoprecipitation assay data indicated that AURKA was associated with HDM2 in a protein complex. The in vitro kinase assay using recombinant AURKA and HDM2 proteins followed by co-immunoprecipitation revealed that AURKA directly interacts and phosphorylates HDM2 protein in vitro. The activation of HDM2 by AURKA led to induction of P53 ubiquitination and attenuation of cisplatin-induced activation of P53 in gastric cancer cells. Inhibition of AURKA using an investigational small-molecule specific inhibitor, alisertib, decreased the HDM2 protein level and induced P53 transcriptional activity. These effects markedly decreased cell survival in vitro and xenograft tumor growth in vivo. Notably, analysis of immunohistochemistry on tissue microarrays revealed significant overexpression of AURKA and HDM2 in human gastric cancer samples (P < 0.05). Conclusion: Collectively, our novel findings indicate that AURKA promotes tumor growth and cell survival through regulation of HDM2-induced ubiquitination and inhibition of P53. Clin Cancer Res; 20(1); 76-86.

AB - Purpose: Suppression of P53 (tumor protein 53) transcriptional function mediates poor therapeutic response in patients with cancer. Aurora kinase A (AURKA) and human double minute 2 (HDM2) are negative regulators of P53. Herein, we examined the role of AURKA in regulating HDM2 and its subsequent effects on P53 apoptotic function in gastric cancer. Experimental Design: Primary tumors and in vitro gastric cancer cell models with overexpression or knockdown of AURKA were used. The role of AURKA in regulating HDM2 and cell survival coupled with P53 expression and activity were investigated. Results: Overexpression of AURKA enhanced the HDM2 protein level; conversely, knockdown of endogenous AURKA decreased expression of HDM2 in AGS and SNU-1 cells. Dual co- immunoprecipitation assay data indicated that AURKA was associated with HDM2 in a protein complex. The in vitro kinase assay using recombinant AURKA and HDM2 proteins followed by co-immunoprecipitation revealed that AURKA directly interacts and phosphorylates HDM2 protein in vitro. The activation of HDM2 by AURKA led to induction of P53 ubiquitination and attenuation of cisplatin-induced activation of P53 in gastric cancer cells. Inhibition of AURKA using an investigational small-molecule specific inhibitor, alisertib, decreased the HDM2 protein level and induced P53 transcriptional activity. These effects markedly decreased cell survival in vitro and xenograft tumor growth in vivo. Notably, analysis of immunohistochemistry on tissue microarrays revealed significant overexpression of AURKA and HDM2 in human gastric cancer samples (P < 0.05). Conclusion: Collectively, our novel findings indicate that AURKA promotes tumor growth and cell survival through regulation of HDM2-induced ubiquitination and inhibition of P53. Clin Cancer Res; 20(1); 76-86.

UR - http://www.scopus.com/inward/record.url?scp=84892159539&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892159539&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-13-1187

DO - 10.1158/1078-0432.CCR-13-1187

M3 - Article

VL - 20

SP - 76

EP - 86

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 1

ER -