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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 95-100 |
| Number of pages | 6 |
| Journal | European Journal of Pharmacology |
| Volume | 560 |
| Issue number | 2-3 |
| DOIs | |
| State | Published - Apr 10 2007 |
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Keywords
- Apoptosis
- JNK1
- p21
- Proliferation
- Sulindac
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Pharmacology
Cite this
JNK1 is required for sulindac-mediated inhibition of cell proliferation and induction of apoptosis in vitro and in vivo. / Song, Zibo; Tong, Chang; Liang, Jiao; Dockendorff, Ashley; Huang, Chuanshu; Augenlicht, Leonard H.; Yang, Wancai.
In: European Journal of Pharmacology, Vol. 560, No. 2-3, 10.04.2007, p. 95-100.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - JNK1 is required for sulindac-mediated inhibition of cell proliferation and induction of apoptosis in vitro and in vivo
AU - Song, Zibo
AU - Tong, Chang
AU - Liang, Jiao
AU - Dockendorff, Ashley
AU - Huang, Chuanshu
AU - Augenlicht, Leonard H.
AU - Yang, Wancai
PY - 2007/4/10
Y1 - 2007/4/10
N2 - 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.
AB - 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.
KW - Apoptosis
KW - JNK1
KW - p21
KW - Proliferation
KW - Sulindac
UR - http://www.scopus.com/inward/record.url?scp=33847363510&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33847363510&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2007.01.020
DO - 10.1016/j.ejphar.2007.01.020
M3 - Article
C2 - 17292881
AN - SCOPUS:33847363510
VL - 560
SP - 95
EP - 100
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 2-3
ER -