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Frequent overexpression of Aurora Kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions
Author(s) -
Dar Altaf A.,
Zaika Alexander,
Piazuelo Maria B.,
Correa Pelayo,
Koyama Tatsuki,
Belkhiri Abbes,
Washington Kay,
Castells Antoni,
Pera Manuel,
ElRifai Wael
Publication year - 2008
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.23371
Subject(s) - immunohistochemistry , tunel assay , cancer research , immunostaining , aurora kinase , apoptosis , protein kinase b , flow cytometry , gene knockdown , medicine , pathology , biology , cancer , microbiology and biotechnology , cell cycle , biochemistry
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 AKT Ser473 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. Cancer 2008. ©2008 American Cancer Society.