Endopolyploidy in irradiated p53-deficient tumour cell lines: persistence of cell division activity in giant cells expressing Aurora-B kinase.
Recent findings including computerised live imaging suggest that polyploidy cells transiently emerging after severe genotoxic stress (and named 'endopolyploid cells') may have a role in tumour regrowth after anti-cancer treatment. Until now, mostly the factors enabling metaphase were studied in them. Here we investigate the mitotic activities and the role of Aurora-B, in view of potential depolyploidisation of these cells, because Aurora-B kinase is responsible for coordination and completion of mitosis. We observed that endopolyploid giant cells are formed via different means in irradiated p53 tumours, by: (1) division/fusion of daughter cells creating early multi-nucleated cells; (2) asynchronous division/fusion of sub-nuclei of these multi-nucleated cells; (3) a series of polyploidising mitoses reverting replicative interphase from aborted metaphase and forming giant cells with a single nucleus; (4) micronucleation of arrested metaphases enclosing genome fragments; or (5) incomplete division in the multi-polar mitoses forming late multi-nucleated giant cells. We also observed that these activities can release para-diploid cells, although infrequently. While apoptosis typically occurs after a substantial delay in these cells, we also found that approximately 2% of the endopolyploid cells evade apoptosis and senescence arrest and continue some form of mitotic activity. We describe here that catalytically active Aurora-B kinase is expressed in the nuclei of many endopolyploid cells in interphase, as well as being present at the centromeres, mitotic spindle and cleavage furrow during their attempted mitotes. The totally micronucleated giant cells (containing sub-genomic fragments in multiple micronuclei) represented only the minor fraction which failed to undergo mitosis, and Aurora-B was absent from it. These observations suggest that most endopolyploid tumour cells are not reproductively inert and that Aurora-B may contribute to the establishment of resistant tumours post-irradiation.
Erenpreisa
Jekaterina
J
Latvia Biomedicine Research and Study Centre, Riga, Latvia. katrina@biomed.lu.lv
Ivanov
Andrei
A
Wheatley
Sally P
SP
Kosmacek
Elizabeth A
EA
Ianzini
Fiorenza
F
Anisimov
Alim P
AP
Mackey
Michael
M
Davis
Paul J
PJ
Plakhins
Grigorijs
G
Illidge
Timothy M
TM
D000705:Anaphase / Q000528:radiation effects; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002455:Cell Division / Q000528:radiation effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002877:Chromosomes, Human / Q000378:metabolism / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000378:metabolism; D015726:Giant Cells / Q000201:enzymology* / Q000473:pathology* / Q000528:radiation effects; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D014965:X-Rays
D004273:DNA, Neoplasm; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases