Loss of catalase increases malignant mouse keratinocyte cell growth through activation of the stress activated JNK pathway.
A cell line that produces mouse squamous cell carcinoma (6M90) was modified to develop a cell line with an introduced Tet-responsive catalase transgene (MTOC2). We have previously reported that the overexpressed catalase in the MTOC2 cells reverses the malignant phenotype in part by decreasing epidermal growth factor receptor (EGFR) signaling. With this work we expanded the investigation into the differences between these two cell lines. We found that the decreased EGFR pathway activity of the MTOC2 cells is not because of reduced autocrine secretion of an epidermal growth factor (EGF) ligand but rather because of lower basal receptor activity. Phosphorylated levels of the mitogen-activated protein kinase (MAPK) members JNK and p38 were both higher in the 6M90 cells with low catalase when compared with the MTOC2 cell line. Although treatment with an EGFR inhibitor, AG1478, blocked the increased activity of JNK in the 6M90 cells, a similar effect was not observed for p38. Basal levels of downstream c-jun transcription were also found to be higher in the 6M90 cells versus MTOC2 cells. Activated p38 was found to down-regulate the JNK MAPK pathway in the 6M90 cells. However, the 6M90 cells contain constitutively high levels of phosphorylated JNK, generating higher levels of phosphorylated c-jun and total c-jun than those in the MTOC2 cells. Inhibition of JNK activity in the 6M90 cells reduced AP-1 transcription and cell proliferation. The data confirm the inhibitory effects of catalase on tumor cell growth, specifically through a ligand-independent decrease in the stress activated JNK pathway.
Hanke
Neale T
NT
Arizona Cancer Center, University of Arizona, Tucson, AZ 85724-5024, USA.
Finch
Joanne S
JS
Bowden
G Timothy
GT
D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D019076:Transgenes / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D002374:Catalase; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases