Peroxiredoxin I contributes to TRAIL resistance through suppression of redox-sensitive caspase activation in human hepatoma cells.
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.
Song
In-Sung
IS
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Republic of Korea.
Kim
Sun-Uk
SU
Oh
Nang-Su
NS
Kim
Jiyoung
J
Yu
Dae-Yeul
DY
Huang
Song Mei
SM
Kim
Jin-Man
JM
Lee
Dong-Seok
DS
Kim
Nam-Soon
NS
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D054464:Peroxiredoxins / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; D054464:Peroxiredoxins; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8; C093642:SB 203580