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PARP proteins localize to either centrosomes or centromeres and catalyze poly
(ADP-ribosyl)ation of both centrosomal and centromeric proteins (Kanai et al.
2003
; Saxena et al.
2002
) arguing for a possible role of PARP proteins in the
clustering process. On the other hand, centrosome clustering was apparently not
affected by other potent, non-phenanthrene PARP inhibitors (Castiel et al.
2011
),
thereby questioning a specific role for PARP inhibition in the prevention of cen-
trosome clustering.
In addition to drugs, siRNAs to the kinesin KIFC1/HSET, the NDC80 complex
subunit HEC1, aurora B, survivin, sororin, SGOL1, the augmin complex subunits
HAUS3 and FAM29A (also known as HAUS6) as well as ILK and PRC1 lead to
cell death through inhibition of centrosomal clustering in tumor cells with
amplified centrosomes but not in normal cells (Kwon et al.
2008
; Leber et al.
2010
;
Fielding et al.
2011
). Identified in an RNAi screen performed in D. melanogaster
S2 cells, siRNAs to KIFC1/HSET and Myo10 increased the frequency of spindle
multipolarity in human cancer cells harboring supernumerary centrosomes as well
(Kwon et al.
2008
). Especially, KIFC1/HSET might constitute an interesting
therapeutic target as knockdown of the protein had no effect on cell division in
diploid control cells but largely decreased viability of tumor cells with extra
centrosomes by inducing multipolar anaphases and subsequent apoptosis (Kwon
et al.
2008
).
Also, small molecule inhibition of ILK, HEC1, and aurora B suppresses tumor
cell growth in tissue culture as well as in animals (Huang et al.
2007
; Wu et al.
2008
; Wilkinson et al.
2007
; Kalra et al.
2009
). Therefore, induction of multipolar
spindles seems to induce cell death irrespective of the underlying mechanism that
induced them. By contrast, although inhibition of monopolar spindle 1 (MPS1,
also known as TTK), a dual-specificity kinase required for the maintenance of
SAC activation, inhibits centrosomal clustering and induces aberrant cell divisions
in cells with supernumerary centrosomes, it does not cause selective cytotoxicity
in cells with amplified centrosomes compared to cells with a regular centrosome
content (Kwiatkowski et al.
2010
). Therefore, it might be concluded that whereas
SAC inhibition per se equally targets all cells, selective inhibition of centrosomal
clustering through specific targeting may provide a therapeutic window to spe-
cifically target cells with supernumerary centrosomes.
Importantly, prior to cell death, cells with inhibited HEC1 or aurora B have
multipolar spindles, lagging chromosomes and subsequent aneuploidy and polyploidy
(Wu et al.
2008
; Wilkinson et al.
2007
). Therefore, a possible downside of centrosomal
cluster inhibition as a potential treatment approach might be the induction of cell clones
with additional chromosomal abnormalities. On the optimistic side, such a risky
scenario seems relatively unlikely, as multipolar cell division mostly leads to gross
CIN and cell death (Ganem et al.
2009
;Kopsetal.
2004
).
Acknowledgment We apologize to those authors whose work is not cited because of space
limitations. This work was supported by the Deutsche Forschungsgemeinschaft, the Deutsche
Krebshilfe, the Deutsche José Carreras Leukämie-Stiftung and the Interdisciplinary Research
Program of the National Center for Tumor Diseases Heidelberg.
