JNK1 is required for sulindac-mediated inhibition of cell proliferation and induction of apoptosis in vitro and in vivo.
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.
Song
Zibo
Z
Department of Oncology, Albert Einstein Cancer Center, Bronx, NY 10467, USA.
Tong
Chang
C
Liang
Jiao
J
Dockendorff
Ashley
A
Huang
Chuanshu
C
Augenlicht
Leonard H
LH
Yang
Wancai
W
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000502:physiology*; D010766:Phosphorylation; D013467:Sulindac / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D013467:Sulindac; D048055:Mitogen-Activated Protein Kinase 8