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Page 214 Jia et al. Cancer Drug Resist 2019;2:210-24 I http://dx.doi.org/10.20517/cdr.2018.010

directly by dysregulation of centrosome protein levels or indirectly by regulating gene expression of other
proteins.

Gene dosage
As discussed previously, gene dosage may affect centrosome duplication through a balance of the relative
abundance of one or more proteins essential for the assembly of new centrioles and the availability of assembly
sites. Thus, dysregulation of gene dosage for centrosome proteins produce aneuploidy and chromosome
instability. Moreover, there are a close relationship between aneuploidy, chromosome instability and
chemotherapy resistance.

The Aurora A kinase regulates centrosome maturation and separation and thereby play important roles
in spindle assembly and stability. Overexpression of Aurora-A kinase induces centrosome amplification
and chromosomal instability that create tumor cell heterogeneity, thus is associated with acquired drug
resistance .
[56]

PLK4 is a key component of the centrosome. Dysregulation of PLK4 activity causes loss of centrosome
numeral integrity. Its overexpression is responsible centrosome amplification and contributes to resistance
to tamoxifen and trastuzumab .
[57]

Mitotic slippage
Chemotherapy is commonly used in order to induce cell death or to prevent proliferation of cancer cells by
impairing spindle function and chromosome segregation. However sometimes cancer cells evade cell death
for those that are arrested in mitosis . Instead these cells leave mitosis without completing a normal cell
[58]
division and become tetraploid. This phenomenon is called mitotic slippage. The examples can be seen in
the drugs that target microtubule assembly (nocodazole, vincristine) or the disassembly (taxol or paclitaxel).

Avoiding apoptosis through mitotic slippage in cancer cells is thought to be a major mechanism contributing
to cancer drug resistance. An interesting recent study provides insight into the mechanism of mitotic
slippage. BH3-only pro-apoptotic proteins are necessary to initiate the molecular process of apoptosis in cells
undergoing perturbed mitosis . NEK2 conferred drug resistance is associated with decreased apoptosis .
[60]
[59]
Furthermore, overexpression of NEK2 suppressed the expression of the BH3-only genes BAD and PUMA
and upregulated the expression of pro-survival genes BCL-xL and MCL-1, indicating a possible role of NEK2
in cancer drug resistance via mitotic slippage.

Phosphorylation at S69 of BIM, which is also a BH3-only protein, leads to its ubiquitin-dependent
degradation . During mitotic arrest, BIM is known to be heavily by Aurora A kinase, which could result
[61]
in mitotic slippage.

Centrosome protein CEP55 was found to have a role in promoting mitotic slippage, which again is mediated
by the Bcl2 family proteins in breast cancer . In breast cancer patients, high-level expression of CEP55
[62]
associates with chemotherapeutic resistance, particularly to docetaxel. Similarly, docetaxel induces spindle
multipolarity, higher KIFC1 expression might counteract this effect to prevent cell death and enable bipolar
spindle formation through centrosome clustering .
[55]
These studies demonstrated that centrosome proteins regulate gene expression of apoptotic/anti-apoptotic
genes to induce cancer drug resistance.

Regulation of drug transporters by centrosome proteins
A recent study demonstrates that overexpression of NEK2 and drug resistance are closely correlated in
other cancers through activation of efflux drug pumps [57,60] . Overexpression of NEK2 upregulated ABC