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Apoptosis

, Volume 17, Issue 12, pp 1275–1286 | Cite as

Celastrol inhibits growth and induces apoptotic cell death in melanoma cells via the activation ROS-dependent mitochondrial pathway and the suppression of PI3K/AKT signaling

  • Ju-Hye Lee
  • Yeong-Seon Won
  • Ki-Hun Park
  • Mi-Kyung Lee
  • Hirofumi Tachibana
  • Koji Yamada
  • Kwon-Il SeoEmail author
Original Paper

Abstract

Celastrol has been reported to possess anticancer effects in various cancers; however, the precise mechanism underlying ROS-mediated mitochondria-dependent apoptotic cell death triggered by celastrol treatment in melanoma cells remains unknown. We showed that celastrol effectively induced apoptotic cell death and inhibited tumor growth using tissue culture and in vivo models of B16 melanoma. In addition to apoptotic cell death in B16 cells, several apoptotic events such as PARP cleavage and activation of caspase were confirmed. Pretreatment with caspase inhibitor modestly attenuated the celastrol-induced increase in PARP cleavage and sub-G1 cell population, implying that caspases play a partial role in celastrol-induced apoptosis. Moreover, ROS generation was detected following celastrol treatment. Blocking of ROS accumulation with ROS scavengers resulted in inhibition of celastrol-induced Bcl-2 family-mediated apoptosis, indicating that celastrol-induced apoptosis involves ROS generation as well as an increase in the Bax/Bcl-2 ratio leading to release of cytochrome c and AIF. Importantly, silencing of AIF by transfection of siAIF into cells remarkably attenuated celastrol-induced apoptotic cell death. Moreover, celastrol inhibited the activation of PI3K/AKT/mTOR signaling cascade in B16 cells. Our data reveal that celastrol inhibits growth and induces apoptosis in melanoma cells via the activation of ROS-mediated caspase-dependent and -independent pathways and the suppression of PI3K/AKT signaling.

Keywords

Celastrol Reactive oxygen species Apoptosis Apoptosis inducing factor B16 melanoma 

Notes

Acknowledgments

This work was supported by National Research Foundation of Korean Grant funded by the Korean Government, Ministry of Education, Science and Technology (NRF-2010-355-F00049).

Conflict of interest

The authors declare that they no conflict of interest.

Supplementary material

10495_2012_767_MOESM1_ESM.pptx (539 kb)
Supplementary material 1 (PPTX 538 kb)
10495_2012_767_MOESM2_ESM.docx (16 kb)
Supplementary material 2 (DOCX 16 kb)

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Ju-Hye Lee
    • 1
  • Yeong-Seon Won
    • 1
  • Ki-Hun Park
    • 2
  • Mi-Kyung Lee
    • 1
  • Hirofumi Tachibana
    • 3
  • Koji Yamada
    • 3
  • Kwon-Il Seo
    • 1
    Email author
  1. 1.Department of Food and NutritionSunchon National UniversitySuncheonRepublic of Korea
  2. 2.Department of Environ BiotechnologyGyeongsang National UniversityGyeongnamRepublic of Korea
  3. 3.Department of Bioscience and BiotechnologyKyushu UniversityFukuokaJapan

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