Rottlerin induces heme oxygenase-1 (HO-1) up-regulation through reactive oxygen species (ROS) dependent and PKC delta-independent pathway in human colon cancer HT29 cells.
Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated by its substrate heme and diverse stimuli. The induction of HO-1 gene expression is one of the important events in cellular response to pro-oxidative and pro-inflammatory insults. In this study, the effect of rottlerin, a putative PKC delta inhibitor, on HO-1 expression in HT29 human colon cancer cells was investigated. Rottlerin-induced HO-1 at both protein and mRNA levels in a dose- and time-dependent manner. Rottlerin-mediated HO-1 induction was abrogated in the presence of N-acetylcysteine (NAC) or glutathione (GSH). Rottlerin induced nuclear translocation of NF-E2-related factor 2 (Nrf2) and increased antioxidant response element (ARE)-driven transcriptional activity. Additionally, rottlerin activated p38 mitogen-activated protein kinase (MAPK) and ERK. The pharmacological inhibition of ERK and p38 MAPK inhibited rottlerin-induced HO-1 up-regulation. However, suppression of protein kinase C delta (PKC delta) expression by siRNA or overexpression of WT-PKC delta did not abrogate the rottlerin-mediated induction of HO-1. These results suggest that rottlerin induces up-regulation of HO-1 via PKC delta-independent pathway. Taken together, the present study identified rottlerin as a novel inducer of HO-1 expression and identified the mechanisms involved in this process.
Park
Eun Jung
EJ
Department of Immunology, Keimyung University, Taegu, South Korea.
Lim
Jun Hee
JH
Nam
Sung Il
SI
Park
Jong Wook
JW
Kwon
Taeg Kyu
TK
D000098:Acetophenones / Q000494:pharmacology*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019073:HT29 Cells; D051547:Heme Oxygenase-1 / Q000235:genetics*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000098:Acetophenones; D001578:Benzopyrans; D051267:NF-E2-Related Factor 2; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C085746:rottlerin; D008156:Luciferases; D051547:Heme Oxygenase-1; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases