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

Sun J, Knickelbein K, He K, Chen D, Dudgeon C, Shu Y, Yu J, Zhang L
Mol Cancer Ther. 2014 13 (5): 1298-308

PMID: 24563542 · PMCID: PMC4013266 · DOI:10.1158/1535-7163.MCT-13-0846

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.

MeSH Terms (21)

Animals Apoptosis Apoptosis Regulatory Proteins Aurora Kinases Cell Line, Tumor Cell Survival Colonic Neoplasms Disease Models, Animal Drug Resistance, Neoplasm Female Humans Mice NF-kappa B Polyploidy Protein Kinase Inhibitors Proto-Oncogene Proteins Proto-Oncogene Proteins c-akt RNA Interference Signal Transduction Tumor Suppressor Protein p53 Xenograft Model Antitumor Assays

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