Role of TOPK in HeLa cancer cells resistance to doxorubicin-mediated apoptosis

T-lymphokine-activated killer celloriginated protein kinase (TOPK) is known to be upregulated in cancer cells, and appears to contribute to cancer cells proliferation and survival. However, the molecular mechanism by which TOPK regulates cancer cells survival still remains elusive. Here we show that TOPK directly interacted with, and phosphorylated IB at Ser-32 leading to p65 nuclear translocation and NF-B activation. We also revealed that doxorubicin promoted the interaction between non-phosphorylated or phosphorylated TOPK and IB, and that TOPK-mediated IB phosphorylation was enhanced in response to doxorubicin. Also, exogenously overexpressed TOPK augmented transcriptional activity driven by either NFB or inhibitor of apoptosis protein 2 (cIAP2) promoters. On the other hand, NF-B activity including IB phosphorylation and p65 nuclear translocation, as well as cIAP2 gene expression was markedly diminished in TOPK knockdown HeLa cervical cancer cells. Moreover, doxorubicin-mediated apoptosis was noticeably increased in TOPK knockdown HeLa cells, compared with control cells, which resulted from caspasedependent signaling pathways. These results demonstrate that TOPK is a molecular target of doxorubicin and mediates doxorubicin chemoresistance of HeLa cells, suggesting a novel mechanism for TOPK barrier of doxorubicin-mediated cervical cancer cell apoptosis.