Table 2 TOPK is a pro-oncogenic kinase with chemotherapeutic potential

From: T-LAK cell-originated protein kinase (TOPK): an emerging target for cancer-specific therapeutics

Characteristic

Mechanism

References

Tumour dissemination

PRPK phosphorylation (Ser250) by TOPK regulates p53- and Akt-mediated activation of tumour cell migration and invasion.

29

Proliferative potential, replicative immortality

TOPK expression is regulated by a negative feedback loop via FLT3 expression and CEBPA phosphorylation.

28

Apoptotic resistance

TOPK binds histone H2A, promoting nuclear colocalisation and phosphorylation of γH2AX.

32

 

TOPK and PRX1 colocalise in the nucleus. TOPK regulates PRX1 peroxidase activity by phosphorylation at Ser32.

33

Cell death signalling

TOPK suppresses p53-mediated transcription of pro-apoptotic intermediates in tumour cells.

28, 36

 

TOPK confers resistance to TRAIL-induced apoptotic cell death via NF-κB mediated transcriptional activity.

37

 

TOPK directly phosphorylates IκBα at Ser-32 and promotes RelA nuclear translocation. Overexpression enhances NF-κB and cIAP2 transcriptional activity.

38

Oxidative damage

TOPK activation protects against cell death by enhancing the Bcl-2/Bax ratio.

34

 

pAkt and pTOPK colocalise in neural cells following ischaemia, increasing expression of peroxiredoxins-1 and 2, and thioredoxin-1.

35

 

TOPK suppresses JNK/p38 signal pathway activation during exposure to oxidising conditions.

22

DNA damage

TOPK expression in cancer cell lines promotes resolution of chromosomal errors following DNA damage.

40

 

TOPK expression is regulated by E2F and CREB/ATF-mediated transcription. TOPK directly interacts with p53 and promotes molecular destabilisation.

39

  1. Increased TOPK expression in cancer cells promotes the activation of multiple pathways involved in sustained growth and proliferation, evasion of cell death, invasive potential and metastatic growth. Inhibition of TOPK activity restores cellular responses to cell death signalling and replicative control mechanisms, as well as overcoming oncogenic chemoresistance by sensitising cancer cells to DNA damaging agents.
  2. Key: TOPK T-LAK cell-originated protein kinase, FLT3 fms-like tyrosine kinase 3 (CD135), CEBPA CCAAT/enhancer-binding protein alpha, NF-κB nuclear factor kappa light chain enhancer of activated B cells, TRAIL TNF-related apoptosis-inducing ligand, IκBα inhibitor of kappa B, CREB/ATF cAMP response element binding protein activating transcription factor, PRPK p53-related protein kinase, PRX1 Peroxiredoxin 1.
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