title: 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.affiliation: Authors' Affiliations: University of Pittsburgh Cancer Institute; Departments of Pharmacology and Chemical Biology and Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Medical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Kyle
authors.initials: K
authors.lastname: Knickelbein
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.forename: Dongshi
authors.initials: D
authors.lastname: Chen
authors.forename: Crissy
authors.initials: C
authors.lastname: Dudgeon
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Shu
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D064127:Aurora Kinases / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D064127:Aurora Kinases; D051057:Proto-Oncogene Proteins c-akt