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 Seo
  • Seung-Woo Hong
  • Jae-Sik Shin
  • In-Chul Park
  • Nam-Joo Hong
  • Dae-Jin Kim
  • Won-Keun Lee
  • Wang-Jae Lee
  • Dong-Hoon Jin
  • Myeong-Sok Lee
Original Paper

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 

Abbreviations

NSAIDs

Non-steroidal anti-inflammatory drugs

IKKβ

IκB kinase β

JNK1

c-Jun NH2-terminal kinase 1

COX

Cyclooxygenase

MAPK

Matogen-activated protein kinase

NF-κB

Nuclear factor kappa B

IκB

Inhibitory kappa B

Supplementary material

10495_2009_367_MOESM1_ESM.pdf (61 kb)
Supplementary material 1 (PDF 60 kb)

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • A-Mi Seo
    • 1
  • Seung-Woo Hong
    • 2
    • 3
    • 4
  • Jae-Sik Shin
    • 3
    • 4
  • In-Chul Park
    • 5
  • Nam-Joo Hong
    • 6
  • Dae-Jin Kim
    • 7
  • Won-Keun Lee
    • 2
  • Wang-Jae Lee
    • 3
    • 4
  • Dong-Hoon Jin
    • 3
  • Myeong-Sok Lee
    • 1
  1. 1.Research Center for Women’s Diseases, Division of Biological SciencesSookmyung Women’s UniversitySeoulKorea
  2. 2.Department of Biological SciencesMyongji UniversityYonginKorea
  3. 3.Department of Anatomy and Tumor Immunity Medical Research CenterSeoul National University College of MedicineSeoulKorea
  4. 4.Cancer Research InstituteSeoul National University College of MedicineSeoulKorea
  5. 5.Laboratory of Functional GenomicsKorea Institute of Radiological and Medical SciencesSeoulKorea
  6. 6.School of BiotechnologyYeungnam UniversityDaedong, Gyungsan CityKorea
  7. 7.Department of Anatomy, College of MedicineChung-Ang UniversitySeoulRepublic of Korea

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