JNK1 is required for sulindac-mediated inhibition of cell proliferation and induction of apoptosis in vitro and in vivo

Zibo Song, Chang Tong, Jiao Liang, Ashley Dockendorff, Chuanshu Huang, Leonard H. Augenlicht, Wancai Yang

Research output: Contribution to journalArticle

15 Scopus citations

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 languageEnglish (US)
Pages (from-to)95-100
Number of pages6
JournalEuropean Journal of Pharmacology
Volume560
Issue number2-3
DOIs
StatePublished - Apr 10 2007

Keywords

  • Apoptosis
  • JNK1
  • Proliferation
  • Sulindac
  • p21

ASJC Scopus subject areas

  • Pharmacology

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