ZM 447439 inhibition of aurora kinase induces Hep2 cancer cell apoptosis in three-dimensional culture.

Abstract

Mitotic Aurora kinases are essential for accurate chromosome segregation during cell division. Forced overexpression of Aurora kinase results in centrosome amplification and multipolar spindles, causing aneuploidy, a hallmark of cancer. ZM447439 (ZM), an Aurora selective ATP-competitive inhibitor, interferes with the spindle integrity checkpoint and chromosome segregation. Here, we showed that inhibition of Aurora kinase by ZM reduced histone H3 phosphorylation at Ser10 in Hep2 carcinoma cells. Multipolar spindles were induced in these ZM-treated G(2)/M-arrested cells with accumulation of 4N/8N DNA, similar to cells with genetically suppressed Aurora-B. Cells subsequently underwent apoptosis, as assessed by cleavage of critical apoptotic associated protein PARP. Hep2 cells formed a tumor-like cell mass in 3-dimensional matrix culture; inhibition of Aurora kinase by ZM either destructed the preformed cell mass or prevented its formation, by inducing apoptotic cell death as stained for cleaved caspase-3. Lastly, ZM inhibition of Aurora kinase was potently in association with decrease of Akt phosphorylation at Ser473 and its substrates GSK3alpha/beta phosphorylation at Ser21 and Ser9. Together, we demonstrated that Aurora kinase served as a potential molecular target of ZM for more selective therapeutic cancer treatment.

• Authors: Zi-Jie Long, Jie Xu, Min Yan, Jian-Gang Zhang, Zhong Guan, Da-Zhi Xu, Xian-Ren Wang, Jine Yao, Fei-Meng Zheng, Guo-Liang Chu, Jun-Xia Cao, Yi-Xin Zeng, Quentin Liu
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 7 Issue 10 Pg. 1473-9 (May 15 2008) ISSN: 1551-4005 [Electronic] United States
• PMID: 18418083 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline
• Benzamides
• COL11A2 protein, human
• Collagen Type XI
• Histones
• Quinazolines
• RNA, Small Interfering
• AURKB protein, human
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Apoptosis (drug effects)
• Aurora Kinase B
• Aurora Kinases
• Benzamides (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromosome Segregation (drug effects)
• Collagen Type XI (metabolism)
• Flow Cytometry
• Fluorescent Antibody Technique
• Histones (metabolism)
• Humans
• Immunoprecipitation
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Quinazolines (pharmacology)
• RNA, Small Interfering (genetics)