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.