Requirement of T-lymphokine-activated killer cell-originated protein kinase for TRAIL resistance of human HeLa cervical cancer cells.
T-lymphokine-activated killer cell-originated protein kinase (TOPK) appears to be highly expressed in various cancer cells and to play an important role in maintaining proliferation of cancer cells. However, the underlying mechanism by which TOPK regulates growth of cancer cells remains elusive. Here we report that upregulated endogenous TOPK augments resistance of cancer cells to apoptosis induced by tumor necrosis factor-related apoptosis inducing ligand (TRAIL). Stable knocking down of TOPK markedly increased TRAIL-mediated apoptosis of human HeLa cervical cancer cells, as compared with control cells. Caspase 8 or caspase 3 activities in response to TRAIL were greatly incremented in TOPK-depleted cells. Ablation of TOPK negatively regulated TRAIL-mediated NF-kappaB activity. Furthermore, expression of NF-kappaB-dependent genes, FLICE-inhibitory protein (FLIP), inhibitor of apoptosis protein 1 (c-IAP1), or X-linked inhibitor of apoptosis protein (XIAP) was reduced in TOPK-depleted cells. Collectively, these findings demonstrated that TOPK contributed to TRAIL resistance of cancer cells via NF-kappaB activity, suggesting that TOPK might be a potential molecular target for successful cancer therapy using TRAIL.
Kwon
Hyeok-Ran
HR
Department of Biochemistry, College of Medicine, Konyang University, 685 Gasuwon-dong, Seo-gu, Daejeon 302-718, Republic of Korea.
Lee
Ki Won
KW
Dong
Zigang
Z
Lee
Kyung Bok
KB
Oh
Sang-Muk
SM
D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology* / Q000627:therapeutic use
D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; D017346:Protein Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase; D053148:Caspase 3; D053181:Caspase 8