| Abstract | Our previous studies demonstrated that sulindac, a non-steroidal anti-inflammatory drug, suppressed intestinal tumor formation in mouse, which is linked to the induction of wild-type p53-activated fragment 1 (p21WAF1, or p21). Here we showed that sulindac also required c-Jun N-terminal Kinase 1 (JNK1) to inhibit cell proliferation and induce apoptosis in vitro and in vivo. First, sulindac inhibited cell proliferation and induced apoptosis in colon cancer cell lines HCT116 with wild-type p21 or null p21, which were p21-dependent and were also associated with the induction of p21 and phosphorylation of JNK1. Second, sulindac increased apoptosis in JNK1(+/+) and JNK1(-/-) mouse embryonic fibroblast (MEF) cells, but, the increase of apoptosis in JNK1(+/+) cells was more than that in JNK1(-/-) cells. More interestingly, sulindac significantly inhibited cell proliferation in JNK1(+/+) cells, but the inhibition in JNK1(-/-) cells markedly decreased. Further studies indicated that JNK1 was dramatically induced by sulindac in the JNK1(+/+) cells which correlated with the induction of p21. However, the induction of p21 in JNK1(-/-) cells was less than that in JNK1(+/+) cells. Finally, we determined the expression of JNK1 in the intestinal mucosa of Apc(+/-), p21(+/+) mice, and found that sulindac significantly induced JNK1 phosphorylation, corresponding to the induction of p21, both in mRNA and protein levels. Our data indicates that sulindac-mediated proliferation inhibition and apoptosis induction were not only p21-dependent, but also required JNK1. |
| Authors | Zibo Song, Chang Tong, Jiao Liang, Ashley Dockendorff, Chuanshu Huang, Leonard H Augenlicht, Wancai Yang
(Affiliation: Department of Oncology, Albert Einstein Cancer Center, Bronx, NY 10467, USA.)
|
| Journal | European journal of pharmacology
(Eur J Pharmacol)
Vol. 560
Issue 2-3
Pg. 95-100
(Apr 10 2007)
ISSN: 0014-2999 Netherlands |
| PMID | 17292881
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Anti-Inflammatory Agents, Non-Steroidal
- CDKN1A protein, human
- Cyclin-Dependent Kinase Inhibitor p21
- Sulindac
- Mitogen-Activated Protein Kinase 8
|
| Topics |
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
(pharmacology)
- Apoptosis
(drug effects)
- Cell Proliferation
(drug effects)
- Cyclin-Dependent Kinase Inhibitor p21
(physiology)
- HCT116 Cells
- Humans
- Mice
- Mitogen-Activated Protein Kinase 8
(physiology)
- Phosphorylation
- Sulindac
(pharmacology)
|
