Frequent overexpression of Aurora kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions

Altaf A. Dar, Alexander Zaika, Maria B. Piazuelo, Pelayo Correa, Tatsuki Koyama, Abbes Belkhiri, Kay Washington, Antoni Castells, Manuel Pera, Wael El-Rifai

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

BACKGROUND. Upper gastrointestinal adenocarcinomas are a common cause of cancer-related deaths. In this study, the authors investigated the prevalence and biological significance of Aurora Kinase A (AURKA) overexpression in upper gastrointestinal adenocarcinomas. METHODS. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining on tumor tissue microarrays (TMA) were used to study the expression of AURKA in upper gastrointestinal adenocarcinomas. To investigate the biological and signaling impact of AURKA, the authors used multiple in vitro assays that included 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling), cytochrome C release, flow cytometry, luciferase reporter, and Western blot analysis. RESULTS. Frequent overexpression of AURKA transcript in upper gastrointestinal adenocarcinomas was detected compared with normal samples (47%; P = .001). The immunohistochemical analysis of 130 tumors demonstrated moderate-to-strong immunostaining of AURKA in >50% of upper gastrointestinal adenocarcinomas. By using camptothecin as a drug-induced apoptosis in vitro model, the authors demonstrated that the expression of AURKA provided protection against apoptosis to gastrointestinal cancer cells (AGS and RKO) (P = .006) and RIE-1 primary intestinal epithelial cells (P =.001). The AURKA overexpression mediated an increase in phosphorylation of AKTSer473 with an increase in HDM2 level. The shRNA-knockdown of AKT in AURKA-overexpressing cells reversed this effect and showed a significant increase in the p53 protein level, indicating a possible nexus of AURKA/AKT/p53. Indeed, overexpression of AURKA led to a remarkable reduction in the transcription activity of p53, with subsequent reductions in transcript and protein levels of its downstream proapoptotic transcription targets (p21, BAX, NOXA, and PUMA). CONCLUSIONS. Study results indicated that AURKA provides potent antiapoptotic properties to gastrointestinal cells by regulating levels of p53 through the AKT/HDM2 axis.

Original languageEnglish (US)
Pages (from-to)1688-1698
Number of pages11
JournalCancer
Volume112
Issue number8
DOIs
StatePublished - Apr 15 2008
Externally publishedYes

Fingerprint

Aurora Kinase A
Adenocarcinoma
Apoptosis
Camptothecin
Neoplasms
Gastrointestinal Neoplasms
DNA Nucleotidylexotransferase
In Situ Nick-End Labeling
Cytochromes
Luciferases
Small Interfering RNA
Real-Time Polymerase Chain Reaction

Keywords

  • Apoptosis
  • AURKA
  • Barrett
  • Cancer
  • Gastric
  • p53
  • Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Frequent overexpression of Aurora kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions. / Dar, Altaf A.; Zaika, Alexander; Piazuelo, Maria B.; Correa, Pelayo; Koyama, Tatsuki; Belkhiri, Abbes; Washington, Kay; Castells, Antoni; Pera, Manuel; El-Rifai, Wael.

In: Cancer, Vol. 112, No. 8, 15.04.2008, p. 1688-1698.

Research output: Contribution to journalArticle

Dar, AA, Zaika, A, Piazuelo, MB, Correa, P, Koyama, T, Belkhiri, A, Washington, K, Castells, A, Pera, M & El-Rifai, W 2008, 'Frequent overexpression of Aurora kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions', Cancer, vol. 112, no. 8, pp. 1688-1698. https://doi.org/10.1002/cncr.23371
Dar, Altaf A. ; Zaika, Alexander ; Piazuelo, Maria B. ; Correa, Pelayo ; Koyama, Tatsuki ; Belkhiri, Abbes ; Washington, Kay ; Castells, Antoni ; Pera, Manuel ; El-Rifai, Wael. / Frequent overexpression of Aurora kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions. In: Cancer. 2008 ; Vol. 112, No. 8. pp. 1688-1698.
@article{b1b15c6a269c49f3bb90069ce1f96f86,
title = "Frequent overexpression of Aurora kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions",
abstract = "BACKGROUND. Upper gastrointestinal adenocarcinomas are a common cause of cancer-related deaths. In this study, the authors investigated the prevalence and biological significance of Aurora Kinase A (AURKA) overexpression in upper gastrointestinal adenocarcinomas. METHODS. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining on tumor tissue microarrays (TMA) were used to study the expression of AURKA in upper gastrointestinal adenocarcinomas. To investigate the biological and signaling impact of AURKA, the authors used multiple in vitro assays that included 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling), cytochrome C release, flow cytometry, luciferase reporter, and Western blot analysis. RESULTS. Frequent overexpression of AURKA transcript in upper gastrointestinal adenocarcinomas was detected compared with normal samples (47{\%}; P = .001). The immunohistochemical analysis of 130 tumors demonstrated moderate-to-strong immunostaining of AURKA in >50{\%} of upper gastrointestinal adenocarcinomas. By using camptothecin as a drug-induced apoptosis in vitro model, the authors demonstrated that the expression of AURKA provided protection against apoptosis to gastrointestinal cancer cells (AGS and RKO) (P = .006) and RIE-1 primary intestinal epithelial cells (P =.001). The AURKA overexpression mediated an increase in phosphorylation of AKTSer473 with an increase in HDM2 level. The shRNA-knockdown of AKT in AURKA-overexpressing cells reversed this effect and showed a significant increase in the p53 protein level, indicating a possible nexus of AURKA/AKT/p53. Indeed, overexpression of AURKA led to a remarkable reduction in the transcription activity of p53, with subsequent reductions in transcript and protein levels of its downstream proapoptotic transcription targets (p21, BAX, NOXA, and PUMA). CONCLUSIONS. Study results indicated that AURKA provides potent antiapoptotic properties to gastrointestinal cells by regulating levels of p53 through the AKT/HDM2 axis.",
keywords = "Apoptosis, AURKA, Barrett, Cancer, Gastric, p53, Survival",
author = "Dar, {Altaf A.} and Alexander Zaika and Piazuelo, {Maria B.} and Pelayo Correa and Tatsuki Koyama and Abbes Belkhiri and Kay Washington and Antoni Castells and Manuel Pera and Wael El-Rifai",
year = "2008",
month = "4",
day = "15",
doi = "10.1002/cncr.23371",
language = "English (US)",
volume = "112",
pages = "1688--1698",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "8",

}

TY - JOUR

T1 - Frequent overexpression of Aurora kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions

AU - Dar, Altaf A.

AU - Zaika, Alexander

AU - Piazuelo, Maria B.

AU - Correa, Pelayo

AU - Koyama, Tatsuki

AU - Belkhiri, Abbes

AU - Washington, Kay

AU - Castells, Antoni

AU - Pera, Manuel

AU - El-Rifai, Wael

PY - 2008/4/15

Y1 - 2008/4/15

N2 - BACKGROUND. Upper gastrointestinal adenocarcinomas are a common cause of cancer-related deaths. In this study, the authors investigated the prevalence and biological significance of Aurora Kinase A (AURKA) overexpression in upper gastrointestinal adenocarcinomas. METHODS. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining on tumor tissue microarrays (TMA) were used to study the expression of AURKA in upper gastrointestinal adenocarcinomas. To investigate the biological and signaling impact of AURKA, the authors used multiple in vitro assays that included 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling), cytochrome C release, flow cytometry, luciferase reporter, and Western blot analysis. RESULTS. Frequent overexpression of AURKA transcript in upper gastrointestinal adenocarcinomas was detected compared with normal samples (47%; P = .001). The immunohistochemical analysis of 130 tumors demonstrated moderate-to-strong immunostaining of AURKA in >50% of upper gastrointestinal adenocarcinomas. By using camptothecin as a drug-induced apoptosis in vitro model, the authors demonstrated that the expression of AURKA provided protection against apoptosis to gastrointestinal cancer cells (AGS and RKO) (P = .006) and RIE-1 primary intestinal epithelial cells (P =.001). The AURKA overexpression mediated an increase in phosphorylation of AKTSer473 with an increase in HDM2 level. The shRNA-knockdown of AKT in AURKA-overexpressing cells reversed this effect and showed a significant increase in the p53 protein level, indicating a possible nexus of AURKA/AKT/p53. Indeed, overexpression of AURKA led to a remarkable reduction in the transcription activity of p53, with subsequent reductions in transcript and protein levels of its downstream proapoptotic transcription targets (p21, BAX, NOXA, and PUMA). CONCLUSIONS. Study results indicated that AURKA provides potent antiapoptotic properties to gastrointestinal cells by regulating levels of p53 through the AKT/HDM2 axis.

AB - BACKGROUND. Upper gastrointestinal adenocarcinomas are a common cause of cancer-related deaths. In this study, the authors investigated the prevalence and biological significance of Aurora Kinase A (AURKA) overexpression in upper gastrointestinal adenocarcinomas. METHODS. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining on tumor tissue microarrays (TMA) were used to study the expression of AURKA in upper gastrointestinal adenocarcinomas. To investigate the biological and signaling impact of AURKA, the authors used multiple in vitro assays that included 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling), cytochrome C release, flow cytometry, luciferase reporter, and Western blot analysis. RESULTS. Frequent overexpression of AURKA transcript in upper gastrointestinal adenocarcinomas was detected compared with normal samples (47%; P = .001). The immunohistochemical analysis of 130 tumors demonstrated moderate-to-strong immunostaining of AURKA in >50% of upper gastrointestinal adenocarcinomas. By using camptothecin as a drug-induced apoptosis in vitro model, the authors demonstrated that the expression of AURKA provided protection against apoptosis to gastrointestinal cancer cells (AGS and RKO) (P = .006) and RIE-1 primary intestinal epithelial cells (P =.001). The AURKA overexpression mediated an increase in phosphorylation of AKTSer473 with an increase in HDM2 level. The shRNA-knockdown of AKT in AURKA-overexpressing cells reversed this effect and showed a significant increase in the p53 protein level, indicating a possible nexus of AURKA/AKT/p53. Indeed, overexpression of AURKA led to a remarkable reduction in the transcription activity of p53, with subsequent reductions in transcript and protein levels of its downstream proapoptotic transcription targets (p21, BAX, NOXA, and PUMA). CONCLUSIONS. Study results indicated that AURKA provides potent antiapoptotic properties to gastrointestinal cells by regulating levels of p53 through the AKT/HDM2 axis.

KW - Apoptosis

KW - AURKA

KW - Barrett

KW - Cancer

KW - Gastric

KW - p53

KW - Survival

UR - http://www.scopus.com/inward/record.url?scp=42149088289&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42149088289&partnerID=8YFLogxK

U2 - 10.1002/cncr.23371

DO - 10.1002/cncr.23371

M3 - Article

VL - 112

SP - 1688

EP - 1698

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 8

ER -