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The MEK/ERK pathway mediates COX‐2‐selective NSAID‐induced apoptosis and induced COX‐2 protein expression in colorectal carcinoma cells
Author(s) -
Elder Douglas J.E.,
Halton Dawn E.,
Playle Laura C.,
Paraskeva Christos
Publication year - 2002
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10330
Subject(s) - mapk/erk pathway , kinase , protein kinase a , p38 mitogen activated protein kinases , mek inhibitor , apoptosis , cancer research , mitogen activated protein kinase , signal transduction , mitogen activated protein kinase kinase , medicine , microbiology and biotechnology , biology , biochemistry
Nonsteroidal antiinflammatory drugs (NSAIDs) can prevent colorectal tumorigenesis in humans and in rodents. In vitro and in vivo studies indicate that one of their principal antineoplastic avenues is the induction of apoptosis. We have shown previously that NS‐398, which selectively inhibits cyclooxygenase‐2 (COX‐2) over cyclooxygenase‐1, induces apoptosis of colorectal tumour cells and elevates COX‐2 protein expression. Here, we have determined that the extracellular signal‐regulated kinase kinase (MEK)/extracellular signal‐regulated kinase (ERK) pathway mediates these effects of NS‐398. Treatment of HT29 colorectal carcinoma cells with 75 μM NS‐398 caused activation of ERK‐1/‐2 but not of the p38 and c‐Jun N‐terminal kinase (JNK) mitogen‐activated protein kinases. This was apparent at 24 hr and maintained at 72 hr. U0126, a specific inhibitor of the ERK‐activating kinases MEK‐1/‐2, prevented the activation of ERK induced by NS‐398 and blocked the increase in COX‐2 protein expression seen when HT29 cells were treated with NS‐398 alone. The activation of ERK by NS‐398 preceded and accompanied a decrease in attached cell yield and an increase in apoptosis. U0126 dose‐dependently protected HT29 cells from these antiproliferative effects of NS‐398, indicating an antiproliferative role for sustained ERK‐1/‐2 activation in response to this NSAID. These results point to a key role for the MEK/ERK signalling pathway in mediating the effects of a COX‐2‐selective NSAID on colorectal carcinoma cells. © 2002 Wiley‐Liss, Inc.