Carcinogenesis Advance Access published online on April 30, 2009
Carcinogenesis, 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
1 Genome Research Center
2 Disease Model Research Center, KRIBB, Daejeon 305-806, Republic of Korea
3 Graduate School of Biotechnology, Kyung Hee University, Yongin, Kyunggi-Do 449-701, Republic of Korea
4 Department of Pathology, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea
5 College of Natural Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea
Address correspondence to: Nam-Soon Kim, Ph.D. and Dong-Seok Lee, Ph.D. Genome Research Center, KRIBB, P.O. Box 115 Yusong, Daejeon 305-806, College of Natural Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea. Tel: 82-42-879-8112, 82-53-950-7366; Fax: 82-42-879-8119, 82-53-943-6925; E-mail: nskim37{at}kribb.re.kr, 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 I (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.
* These authors contributed equally to this work.
Received November 28, 2008; revised April 8, 2009; accepted April 25, 2009.