NEDD9 depletion destabilizes Aurora A kinase and heightens the efficacy of Aurora A inhibitors: implications for treatment of metastatic solid tumors.

Abstract

Aurora A kinase (AURKA) is overexpressed in 96% of human cancers and is considered an independent marker of poor prognosis. While the majority of tumors have elevated levels of AURKA protein, few have AURKA gene amplification, implying that posttranscriptional mechanisms regulating AURKA protein levels are significant. Here, we show that NEDD9, a known activator of AURKA, is directly involved in AURKA stability. Analysis of a comprehensive breast cancer tissue microarray revealed a tight correlation between the expression of both proteins, significantly corresponding with increased prognostic value. A decrease in AURKA, concomitant with increased ubiquitination and proteasome-dependent degradation, occurs due to depletion or knockout of NEDD9. Reexpression of wild-type NEDD9 was sufficient to rescue the observed phenomenon. Binding of NEDD9 to AURKA is critical for AURKA stabilization, as mutation of S296E was sufficient to disrupt binding and led to reduced AURKA protein levels. NEDD9 confers AURKA stability by limiting the binding of the cdh1-substrate recognition subunit of APC/C ubiquitin ligase to AURKA. Depletion of NEDD9 in tumor cells increases sensitivity to AURKA inhibitors. Combination therapy with NEDD9 short hairpin RNAs and AURKA inhibitors impairs tumor growth and distant metastasis in mice harboring xenografts of breast tumors. Collectively, our findings provide rationale for the use of AURKA inhibitors in treatment of metastatic tumors and predict the sensitivity of the patients to AURKA inhibitors based on NEDD9 expression.

• Authors: Ryan J Ice, Sarah L McLaughlin, Ryan H Livengood, Mark V Culp, Erik R Eddy, Alexey V Ivanov, Elena N Pugacheva
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 10 Pg. 3168-80 (May 15 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23539442 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Adaptor Proteins, Signal Transducing
• Enzyme Inhibitors
• NEDD9 protein, human
• Phosphoproteins
• AURKA protein, human
• Aurka protein, mouse
• Aurora Kinase A
• Aurora Kinases
• Protein Serine-Threonine Kinases
• Proteasome Endopeptidase Complex

Topics

• Adaptor Proteins, Signal Transducing (antagonists & inhibitors, physiology)
• Animals
• Aurora Kinase A
• Aurora Kinases
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Enzyme Inhibitors (therapeutic use)
• Enzyme Stability
• Female
• Humans
• Mice
• Neoplasm Metastasis
• Phosphoproteins (antagonists & inhibitors, physiology)
• Proteasome Endopeptidase Complex (physiology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, chemistry)
• Tumor Burden
• Xenograft Model Antitumor Assays