title: Mitogen-activated protein kinase phosphatase-1 inhibition and sustained extracellular signal-regulated kinase 1/2 activation in camptothecin-induced human colon cancer cell death.
abstract: Camptothecins are commonly used chemotherapeutics; in some models, they enhance signaling via the mitogen-activated protein kinase (MAPK) pathway through effects on upstream kinases. To evaluate the impact of camptothecin (CPT) on MAPKs in human colon cancer, we studied HCT116 and CaCo2 colon cancer cells. We found that HCT116 cells highly express mitogen-activated protein kinase phosphatase-1 (MKP1), which selectively inactivates extracellular signal-regulated kinase (ERK), whereas MKP1 levels were undetectable in CaCo2 cells. CPT did not affect ERK activity in CaCo2 cells, but did induce a striking increase in ERK activity in HCT116 cells in association with a corresponding decrease in MKP1. The reduction in MKP1 expression occurred at a posttranscriptional level and was blocked by the proteasome inhibitor MG132, whereas that CPT-induced downregulation of MKP1 was not due to proteasome-mediated degradation. Treatment of HCT116 cells with CPT induced a sustained activation of nuclear ERK, which was required for CPT-induced apoptosis. P38 and JNK activity were unaffected by CPT, suggesting that the effects of CPT are mediated specifically by ERK. These results suggest that targeting dual-specificity MAPK phosphatases in colon cancer cells may be a viable strategy for optimizing camptothecin-based therapeutic protocols.
authors.affiliation: Division of Radiation Effect; Korea Institute of Radiological & Medical Sciences; Seoul, Korea.
authors.forename: Minyoung
authors.initials: M
authors.lastname: Lee
authors.forename: Sun
authors.initials: S
authors.lastname: Young Kim
authors.forename: Jongguk
authors.initials: J
authors.lastname: Kim
authors.forename: Hak-Su
authors.initials: HS
authors.lastname: Kim
authors.forename: Sang-Man
authors.initials: SM
authors.lastname: Kim
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D002166:Camptothecin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054638:Dual Specificity Phosphatase 1; D046988:Proteasome Endopeptidase Complex; D002166:Camptothecin
keywords: ERK; MKP1; camptothecin; human colon cancer