Aurora kinase inhibition induces PUMA via NF-κB to kill colon cancer cells.

Abstract

Aurora kinases play a key role in mitosis and are frequently overexpressed in a variety of tumor cells. Inhibition of aurora kinases results in mitotic arrest and death of cancer cells, and has been explored as an anticancer strategy. However, how aurora inhibition kills cancer cells is poorly understood. In this study, we found that inhibition of aurora kinases by siRNA or small-molecule inhibitors led to induction of p53 upregulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 family protein, in colorectal cancer cells irrespective of p53 status. Deficiency in PUMA increased polyploidy, improved cell survival, and abrogated mitochondria-mediated apoptosis induced by aurora kinase inhibitors. In response to aurora kinase inhibition, PUMA was directly activated by p65 through the canonical NF-κB pathway following AKT inhibition. Furthermore, PUMA was necessary for the chemosensitization and in vivo antitumor effects of aurora kinase inhibitors in colon cancer cells. These results suggest that PUMA induction mediates the apoptotic response to mitotic arrest imposed by aurora kinase inhibition, and may be a useful indicator for the anticancer activity of aurora kinase inhibitors.

• Authors: Jing Sun, Kyle Knickelbein, Kan He, Dongshi Chen, Crissy Dudgeon, Yongqian Shu, Jian Yu, Lin Zhang
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 5 Pg. 1298-308 (May 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 24563542 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Apoptosis Regulatory Proteins
• BBC3 protein, human
• NF-kappa B
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Tumor Suppressor Protein p53
• Aurora Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis (drug effects, genetics)
• Apoptosis Regulatory Proteins (deficiency, genetics, metabolism)
• Aurora Kinases (antagonists & inhibitors)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Colonic Neoplasms (genetics, metabolism, pathology)
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Female
• Humans
• Mice
• NF-kappa B (metabolism)
• Polyploidy
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins (deficiency, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• RNA Interference
• Signal Transduction (drug effects)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays