Abstract
T-lymphokine-activated killer cell-originated protein kinase (TOPK) is known to be up-regulated in cancer cells and appears to contribute to cancer cell proliferation and survival. However, the molecular mechanism by which TOPK regulates cancer cell survival still remains elusive. Here we show that TOPK directly interacted with and phosphorylated IκBα at Ser-32, leading to p65 nuclear translocation and NF-κB activation. We also revealed that doxorubicin promoted the interaction between nonphosphorylated or phosphorylated TOPK and IκBα and that TOPK-mediated IκBα phosphorylation was enhanced in response to doxorubicin. Also, exogenously overexpressed TOPK augmented transcriptional activity driven by either NF-κB or inhibitor of apoptosis protein 2 (cIAP2) promoters. On the other hand, NF-κB activity including IκBα 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 caspase-dependent 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.
Highlights
The regulatory mechanism of T-lymphokine-activated killer cell-originated protein kinase (TOPK) underlying cancer cell survival remains unknown
We identified that TOPK directly binds to IB␣ and phosphorylates serine-32 residue on IB␣ in response to doxorubicin leading to NF-B activation
We indicated that expression of cIAP2 gene is increased in HeLa cervical cancer cells by doxorubicin treatment, but TOPK depletion abolishes this augmentation via NF-B inhibition
Summary
The regulatory mechanism of TOPK underlying cancer cell survival remains unknown. Results: TOPK directly interacts with and phosphorylates IB␣ at Ser-32. NF-B activity including IB␣ phosphorylation and p65 nuclear translocation, as well as cIAP2 gene expression, was markedly diminished in TOPK knockdown HeLa cervical cancer cells. FEBRUARY 1, 2013 VOLUME 288 NUMBER 5 somerase II and double-stranded DNA break, and elicits its inhibitory activity on tumors [3] This doxorubicin-induced DNA damage leads to target cell death. TOPK in Chemoresistance to Doxorubicin-mediated Apoptosis ously, we showed that TOPK confers TRAIL resistance to cancer cells [23] These reports suggest a role for TOPK in cancer cell proliferation and survival. We reveal that TOPK is a novel target molecule in response to doxorubicin and that TOPK directly interacts with and phosphorylates IB␣ at Ser-32, leading to subsequent NF-B activation. We provide evidence that overexpressed TOPK up-regulated expression of cIAP2 gene, one of the NF-B-dependent antiapoptotic genes, and conferred resistance to doxorubicin-induced HeLa cervical cancer cell death
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