Apoptosis

, 12:195

Sulindac-derived reactive oxygen species induce apoptosis of human multiple myeloma cells via p38 mitogen activated protein kinase-induced mitochondrial dysfunction

  • Sung-Keum Seo
  • Hyung-Chahn Lee
  • Sang-Hyeok Woo
  • Hyeon-Ok Jin
  • Doo-Hyun Yoo
  • Su-Jae Lee
  • Sungkwan An
  • Tae-Boo Choe
  • Myung-Jin Park
  • Seok-Il Hong
  • In-Chul Park
  • Chang-Hun Rhee
Article

Abstract

Non-steroidal anti-inflammatory drugs are well known to induce apoptosis of cancer cells independent of their ability to inhibit cyclooxygenase-2, but the molecular mechanism for this effect has not yet been fully elucidated. The purpose of this study was to elucidate the potential signaling components underlying sulindac-induced apoptosis in human multiple myeloma (MM) cells. We found that sulindac induces apoptosis by promoting ROS generation, accompanied by opening of mitochondrial permeability transition pores, release of cytochrome c and apoptosis inducing factor from mitochondria, followed by caspase activation. Bcl-2 cleavage and down-regulation of the inhibitor of apoptosis proteins (IAPs) family including cIAP-1/2, XIAP, and survivin, occurred downstream of ROS production during sulindac-induced apoptosis. Forced expression of survivin and Bcl-2 blocked sulindac-induced apoptosis. Most importantly, sulindac-derived ROS activated p38 mitogen-activated protein kinase and p53. SB203580, a p38 mitogen-activated protein kinase inhibitor, and RNA inhibition of p53 inhibited the sulindac-induced apoptosis. Furthermore, p53, Bax, and Bak accumulated in mitochondria during sulindac-induced apoptosis. All of these events were significantly suppressed by SB203580. Our results demonstrate a novel mechanism of sulindac-induced apoptosis in human MM cells, namely, accumulation of p53, Bax, and Bak in mitochondria mediated by p38 MAPK activation downstream of ROS production.

Keywords

Apoptosis Multiple myeloma NSAIDs Reactive oxygen species 

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Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Sung-Keum Seo
    • 1
  • Hyung-Chahn Lee
    • 1
  • Sang-Hyeok Woo
    • 1
  • Hyeon-Ok Jin
    • 1
  • Doo-Hyun Yoo
    • 1
  • Su-Jae Lee
    • 2
  • Sungkwan An
    • 3
  • Tae-Boo Choe
    • 3
  • Myung-Jin Park
    • 1
  • Seok-Il Hong
    • 1
  • In-Chul Park
    • 1
  • Chang-Hun Rhee
    • 1
  1. 1.Laboratory of Functional GenomicsKorea Institute of Radiological & Medical SciencesSeoulRepublic of Korea
  2. 2.Laboratory of Radiation Experimental TherapeuticsKorea Institute of Radiological & Medical SciencesSeoulRepublic of Korea
  3. 3.Functional Genoproteome Research Centre, Department of Microbial EngineeringKon-Kuk UniversitySeoulRepublic of Korea

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