Carcinogenesis Advance Access originally published online on April 30, 2009
Carcinogenesis 2009 30(7):1106-1114; doi:10.1093/carcin/bgp104
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Peroxiredoxin I contributes to TRAIL resistance through suppression of redox-sensitive caspase activation in human hepatoma cells
Genome Research Center
1 Aging Science Research Center, Korea Research Institute of Bioscience and Biotechnology, PO Box 115 Yusong, Daejeon 305-806, Republic of Korea
2 Graduate School of Biotechnology and Institute of Life Sciences and Resource, Kyung Hee University, Yongin, Kyunggi-Do 449-701, Republic of Korea
3 Department of Pathology, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea
4 School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea
* To whom correspondence should be addressed. Tel: +82 42 879 8112; Fax: +82 42 879 8119; Email: nskim37{at}kribb.re.kr
Correspondence may also be addressed to Dong-Seok Lee. Tel: +82 53 950 7366; Fax: +82 53 943 6925; Email: lee1{at}knu.ac.kr
Reactive oxygen species (ROS) have been implicated in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance of many cancers. We evaluated the role of peroxiredoxin (Prx) I in TRAIL resistance governed by coupling of nicotinamide adenosine dinucleotide phosphate oxidase (Nox)-derived ROS signaling with the p38 mitogen-activated protein kinase (MAPK)/caspase-signaling cascade in liver cancer cells. Upregulated Prx I expression was found in neoplastic regions of human patient liver, and Prx I knockdown resulted in accelerated TRAIL-induced cell death in SK-Hep-1 human hepatoma cells. The TRAIL cytotoxicity by Prx I knockdown was dependent on activation of caspase-8/3 cascades, which was ablated by addition of inhibitors for p38 MAPK, ROS or Nox, suggesting the association with Nox-driven redox signaling. Furthermore, we found that Nox4 was constitutively expressed in both SK-Hep-1 cells and tumor regions of patient livers, knockdown of Nox4 expression could alleviate ROS generation and TRAIL-mediated cytotoxicity. In accordance with previous findings, increased activation of both p38 MAPK and caspase cascades by Prx I knockdown was inhibited by either Nox4 knockdown or SB203580 addition. Collectively, these data suggest that Prx I functions to block propagation of Nox-derived ROS signaling to the p38 MAPK/caspase/cell death cascade during TRAIL treatment and also provides a molecular mechanism by which Prx I contributes to TRAIL resistance in liver cancers.
Abbreviations: As, antisense; CM-H2DCFDA, 5,6-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; DR, death receptor; IgG, immunoglobulin G; MAPK, mitogen-activated protein kinase; β2M, β2-microglobulin; Nox, nicotinamide adenosine dinucleotide phosphate oxidase; PCR, polymerase chain reaction; PI, propidium iodide; Prx, peroxiredoxin; qPCR, quantitative real-time polymerase chain reaction; ROS, reactive oxygen species; S, sense; siRNA, small interfering ribonucleic acid; TBS, Tris-buffered saline; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand
These authors contributed equally to this work. Received November 28, 2008; revised April 8, 2009; accepted April 25, 2009.