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 TOM 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-kappa B activity Furthermore. expression of NF-kappa B-dependent genes, FLICE-inhibitory protein (FLIP), inhibitor of apoptosis protein I (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-kappa B activity, suggesting that TOPK might be a potential molecular target for Successful cancer therapy using TRAIL (C) 2009 Elsevier Inc. All rights reserved.