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. ©2013 AACR.

• Authors: Vikas Sehdev, Ahmed Katsha, Janet Arras, Dunfa Peng, Mohammed Soutto, Jeffrey Ecsedy, Alexander Zaika, Abbes Belkhiri, Wael El-Rifai
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 1 Pg. 76-86 (Jan 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24240108 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Azepines
• MLN 8237
• Pyrimidines
• TP53 protein, human
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• AURKA protein, human
• Aurora Kinase A

Topics

• Adenocarcinoma (drug therapy, enzymology, pathology)
• Animals
• Antineoplastic Agents (pharmacology)
• Aurora Kinase A (antagonists & inhibitors, metabolism)
• Azepines (pharmacology)
• Cell Line, Tumor
• Cell Survival
• Female
• Humans
• Mice
• Mice, Nude
• Phosphorylation
• Proteolysis
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• Pyrimidines (pharmacology)
• Stomach Neoplasms (drug therapy, enzymology, pathology)
• Tumor Suppressor Protein p53 (metabolism)
• Ubiquitination
• Up-Regulation
• Xenograft Model Antitumor Assays