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Occurrence of Aurora A positive multipolar mitoses in distinct molecular classes of colorectal carcinomas and effect of Aurora A inhibition
Author(s) -
Herz Corinna,
Schlürmann Fabienne,
Batarello Daniela,
Fichter Christiane D.,
Schöpflin Anja,
Münch Claudia,
Hauschke Dieter,
Werner Martin,
Lassmann Silke
Publication year - 2012
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20823
Subject(s) - biology , mitosis , centrosome , metaphase , prometaphase , aurora b kinase , nocodazole , aurora inhibitor , cell cycle , prophase , aurora kinase , cancer research , cell , microbiology and biotechnology , cytokinesis , cell division , chromosome , genetics , meiosis , anaphase , gene , cytoskeleton
Aurora A “over‐”expression may induce supernumerary centrosomes, respective multipolar mitoses, and aneuploidy. Here, we examined Aurora A positive multipolar mitoses in aneuploid, microsatellite‐stable (MSS, “CIN‐type”) versus near‐diploid, microsatellite‐instable (MSI, “MIN‐type”) colorectal carcinomas (CRC) and CRC cell lines as well as the effect of Aurora A inhibition in CRC cell lines. In situ, three‐dimensional immunofluorescence (3D‐IF) revealed Aurora A positive multipolar mitoses in both CIN‐ ( n = 8) and MIN‐ ( n = 10) type primary CRCs with similar frequencies (CIN: 27 ± 14%; MIN: 34 ± 14%, P = 0.224). In vitro, Aurora A positive multipolar mitoses were detected in asynchronized or thymidine synchronized CIN‐type (HT29, CaCo‐2), but not MIN‐type (HCT116, DLD‐1) CRC cells. Nocodazole treatment arrested mitotic cells with multiple centrosomal Aurora A signals in CIN‐ and MIN‐type CRC cells, albeit to a lower extent in CaCo‐2 cells. This was associated with concomitant activation of Aurora A (T288 phosphorylation) and Polo‐like kinase 1 (PLK‐1, T210 phosphorylation). Aurora A inhibition by siRNA resulted in increased apoptosis (>50%) in all cell lines, but did not abolish PLK‐1 expression. Double 3D‐IF revealed that Aurora A siRNA treated, still viable CIN‐type (HT29, CaCo‐2) CRC cells were Aurora A negative and mostly in prophase/(pro)metaphase with maintained phosphorylated PLK‐1 T210 expression. Aurora A positive multipolar mitoses occur in both aneuploid, CIN‐ and near‐diploid MIN‐type CRCs. This appears to be largely independent of Aurora A expression alone. Although Aurora A inhibition causes apoptosis in both CIN‐ and MIN‐type CRC cells, remaining PLK‐1 activation by other factors may affect therapeutic Aurora inhibition. © 2011 Wiley Periodicals, Inc.