Original Paper

Apoptosis

, Volume 14, Issue 7, pp 913-922

Sulindac induces apoptotic cell death in susceptible human breast cancer cells through, at least in part, inhibition of IKKβ

  • A-Mi SeoAffiliated withResearch Center for Women’s Diseases, Division of Biological Sciences, Sookmyung Women’s University
  • , Seung-Woo HongAffiliated withDepartment of Biological Sciences, Myongji UniversityDepartment of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of MedicineCancer Research Institute, Seoul National University College of Medicine
  • , Jae-Sik ShinAffiliated withDepartment of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of MedicineCancer Research Institute, Seoul National University College of Medicine
  • , In-Chul ParkAffiliated withLaboratory of Functional Genomics, Korea Institute of Radiological and Medical Sciences
  • , Nam-Joo HongAffiliated withSchool of Biotechnology, Yeungnam University
  • , Dae-Jin KimAffiliated withDepartment of Anatomy, College of Medicine, Chung-Ang University
  • , Won-Keun LeeAffiliated withDepartment of Biological Sciences, Myongji University
  • , Wang-Jae LeeAffiliated withDepartment of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of MedicineCancer Research Institute, Seoul National University College of Medicine
  • , Dong-Hoon JinAffiliated withDepartment of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine Email author 
    • , Myeong-Sok LeeAffiliated withResearch Center for Women’s Diseases, Division of Biological Sciences, Sookmyung Women’s University Email author 

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Abstract

Sulindac is a non-steroidal anti-inflammatory agent with anti-tumor activities that include the induction of apoptosis in various cancer cells and the inhibition malignant transformation. However, the molecular mechanisms underlying these effects are unclear. Recently, it has been shown that sulindac can inhibit NF-κB activation. Here, we demonstrate that sulindac induces apoptotic cell death in susceptible human breast cancer cells through, at least in part, inhibition of IKKβ activity. More specifically, when we compared two different human breast cancer cell lines, Hs578T, which has relatively low basal IKKβ activity, and MDA-MB231, which has relatively high basal IKKβ activity, we found that MDA-MB231 was markedly more sensitive to sulindac-induced apoptosis than Hs578T. This was associated with greater caspase-3 and -9 activity in sulindac-treated MDA-MB231 cells. Using a combination of chemical kinase inhibitors and siRNA-mediated knockdown of specific kinases, we found that sulindac inhibits IKKβ, which, in turn, leads to the p38 MAPK-dependent activation of JNK1. Together, these findings suggest that sulindac induces apoptosis in susceptible human breast cancer cells through, at least in part, the inhibition of IKKβ and the subsequent p38 MAPK-dependent activation of JNK1.

Keywords

NSAIDs Sulindac IKKβ JNK1 P38/MAPK Apoptosis