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transporter family members, including ABCB1 (p-glycoprotein, MDR1), the multidrug resistance protein
ABCC1 (MRP1), and the breast cancer resistant protein ABCG2 (BCRP). High expression of NEK2 promoted
a higher efflux of the hydrophilic eFluxx-ID gold fluorescent dye from cancer cells. Verapamil, an ABC
transporter inhibitor, was able to abrogate part of the NEK2-induced drug resistance by showing a decrease
in colony formation. Downregulation of NEK2 by shRNA decreased the expression of phosphorylated PP1,
AKT, nuclear β-catenin, and ABC transporters.

However, it is also worth to note that drug resistance can also be secondary since chemotherapy or radiation
may induced centrosome abnormalities. This is associated with tumor cell heterogeneity. Accumulations of
centrosome aberrations after nilotinib and imatinib treatment in vitro are associated with mitotic spindle
defects and genetic instability .
[63]

EPIGENETIC REGULATION OF CENTROSOME PROTEIN EXPRESSION
Epigenetic mechanisms that alter functional gene dosage through hyper- or hypo-methylation, and
consequently the abundance of key centrosome precursor molecules, may result in centrosome abnormalities,
spindle defects, aneuploidy and polyploidy.

Although any genetic aberrations of the centrosome proteins contributes to tumorigenesis, alterations of
epigenetic gene regulation are found more frequently as cancer drivers, which include widespread alterations
of CpG island methylation, histone modifications, and dysregulation DNA binding proteins disrupt normal
patterns of gene expression.

Phosphorylation
Many kinases (e.g., CDKs, Aurora A, polo-like kinases, etc.) participate in the regulation of centrosome
duplication even they themselves are also controlled by phosphorylation and dephosphorylation. For instance,
the phosphorylation status of CKAP2 during mitosis is critical for controlling both centrosome biogenesis
and bipolar spindle formation . It has been shown that the Cyclin-Dependent Kinase (CDK)-activating
[64]
phosphatase (CDC25B) localizes to centrosome and involves in the centrosome duplication cycle and in
microtubule nucleation . The activity of CDC25B is positively or negatively regulated by several kinases
[65]
including Aurora A and CHK1 [66,67] . The phosphorylation of CDC25B by Aurora-A locally participate in the
control of the onset of mitosis . Abnormal expression of CDC25B in numerous human tumors might have
[68]
a critical role in centrosome amplification and genomic instability .
[69]
Activities of Aurora-A (AurA) for its cellular function are regulated by different protein-protein interactions
and posttranslational modifications. It has been established that Twist1 has a critical role in promoting
EMT and drug resistance. AURKA phosphorylates Twist1 at three positions (S123, T148 and S184). AURKA-
mediated phosphorylation of Twist1 is crucial for EMT, the cancer stem cell phenotype and drug resistance
togemcitabine . On the other hands, activation of AurA at centrosomes occurs through autophosphorylation
[70]
at the critical activating residue Thr288 . The autophosphorylation is regulated by PLK1 and TPX2 .
[71]
[72]
[73]
PLK4 contains an N-terminal kinase domain (residues 12-284) a C-terminal localization domain (residues 596-898)
and 3 polo box domains, which facilitates oligomerization, targeting, and promotes trans-autophosphorylation.
PLK4 can be directly phosphorylated and activated by stress-activated protein kinase kinase kinases .
[74]
Indeed, tumor-derived SAPKK1/MKK4 mutants induced centrosome amplification under genotoxic
stress (only in p53-negative cells) , which lead to increased resistance to apoptosis, chemotherapy and
[74]
radiotherapy .
[75]
PLK4 is also a substrate of itself (via autophosphorylation). Autophosphorylation of PLK4 results in ubiquitination
and subsequent destruction by the proteasome [76-78] . It has been shown that mutagenesis of ASP-154 in the