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Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2000 Oct; Vol. 6 (10), pp. 4136-41. - Publication Year :
- 2000
-
Abstract
- Sulindac sulfone (Exisulind) induces apoptosis and exhibits cancer chemopreventive activity, but in contrast to sulindac, it does not inhibit cyclooxygenases 1 or 2. We found that sulindac sulfone and two potent derivatives, CP248 and CP461, inhibited the cyclic GMP (cGMP) phosphodiesterases (PDE) 2 and 5 in human colon cells, and these compounds caused rapid and sustained activation of the c-Jun NH2-terminal kinase 1 (JNK1). Rapid activation of stress-activated protein/ERK kinase 1 (SEK1) and mitogen-activated protein kinase kinase kinase (MEKK1), which are upstream of JNK1, was also observed. Other compounds that increase cellular levels of cGMP also activated JNK1, and an inhibitor of protein kinase G (PKG), Rp-8-pCPT-cGMPS, inhibited JNK1 activation by the sulindac sulfone derivatives. Expression of a dominant-negative JNK1 protein inhibited CP248-induced cleavage of poly(ADP-ribose) polymerase, a marker of apoptosis. Thus, it appears that sulindac sulfone and related compounds induce apoptosis, at least in part, through activation of PKG, which then activates the MEKK1-SEK1-JNK1 cascade. These studies also indicate a role for cGMP and PKG in the JNK pathway.
- Subjects :
- Colonic Neoplasms drug therapy
Dose-Response Relationship, Drug
Enzyme Activation
Genes, Dominant
Humans
Mitogen-Activated Protein Kinase 8
Mitogen-Activated Protein Kinase Kinases metabolism
Models, Biological
Protein Serine-Threonine Kinases metabolism
Signal Transduction
Sulindac analogs & derivatives
Time Factors
Tumor Cells, Cultured
Apoptosis
Cyclic GMP metabolism
MAP Kinase Kinase 4
MAP Kinase Kinase Kinase 1
Mitogen-Activated Protein Kinases metabolism
Sulindac pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 6
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 11051267