Leptomycin B, an inhibitor of the nuclear export receptor CRM1, inhibits COX-2 expression.
Cyclooxygenase (COX)-2, the inducible prostaglandin synthase, is overexpressed in cancer and chronic inflammatory diseases. Post-transcriptional regulation of COX-2 mRNA is important in controlling the expression of the COX-2 gene. Here, we report that leptomycin B (LMB), a specific inhibitor of the nuclear export factor CRM1 potently inhibits the stabilization of COX-2 mRNA in MDA-MB-231 human mammary cancer cells. However, COX-2 promoter-driven reporter gene expression is not inhibited by LMB, suggesting that LMB acts at the post-transcriptional level. Subcellular fractionation experiments indicate that LMB inhibited the time-dependent export of COX-2 mRNA into the membrane-bound polysomal compartment at the endoplasmic reticulum. LMB suppressed COX-2 expression by interleukin-1beta in HT-29 human colon cancer cells and in human umbilical vein endothelial cells but had no effect on COX-2 expression induced by Escherichia coli lipopolysaccharide in monocytic THP-1 cells. These data suggest that the nuclear export of COX-2 mRNA may be rate-liming in a cell-specific manner. LMB may be useful to control COX-2 expression in various human diseases in which COX-2 plays a pathogenetic role.
Jang
Byeong-Churl
BC
Center for Vascular Biology, Department of Physiology, University of Connecticut Health Center, Farmington, Connecticut 06030-3501, USA.
Muñoz-Najar
Ursula
U
Paik
Ji-Hye
JH
Claffey
Kevin
K
Yoshida
Minoru
M
Hla
Timothy
T
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms; D002460:Cell Line; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D000097606:Exportin 1 Protein
D000903:Antibiotics, Antineoplastic; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D007527:Isoenzymes; D028884:Karyopherins; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C496540:PTGS2 protein, human; C038753:leptomycin B