Extracellular signal-regulated kinases are involved in the antiapoptotic effect of endothelin-1.
An imbalance between proliferation and apoptosis is an important causal factor for disorders involving abnormal cell accumulation. The role and mechanism of how G protein-coupled receptors are linked to apoptosis are poorly understood. Endothelin-1 (ET-1), a 21-amino acid peptide that binds to G protein-coupled receptors with mitogenic and vasoconstricting activities, suppressed apoptosis of human prostatic smooth muscle cells induced by paclitaxel treatment or serum withdrawal. Serum withdrawal or paclitaxel (1-10 microM) treatment for 48 h resulted in DNA fragmentation, a characteristic of apoptosis. The addition of ET-1 attenuated DNA fragmentation. The attenuating effect of ET-1 on DNA fragmentation was not affected by wortmannin, bisindolylmaleimide I, tyrphostin AG490, or AG1478. However, PD98059, an inhibitor for the extracellular signal-regulated kinase (ERK) kinase, induced apoptosis, potentiated the effect of serum withdrawal on inducing apoptosis, and blocked the antiapoptotic effect of ET-1. The ERK1/2 activity in these cells decreased rapidly after paclitaxel treatment or serum withdrawal, but was maintained at a 2-fold higher level in the presence of ET-1 for at least 4 h. These results suggest that the ERK1/2 pathway is activated by ET-1, and blocking this pathway abolishes the antiapoptotic effect of ET-1.
Wu-Wong
J R
JR
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois, USA. ruth.r.wuwong@abbott.com
Chiou
W J
WJ
Wang
J
J
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020536:Enzyme Activators / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005110:Extracellular Space / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology; D011233:Precipitin Tests; D011467:Prostate / Q000166:cytology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
D000972:Antineoplastic Agents, Phytogenic; D019332:Endothelin-1; D020536:Enzyme Activators; D004247:DNA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel