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Apoptosis

, Volume 19, Issue 4, pp 708–718 | Cite as

β-Caryophyllene oxide potentiates TNFα-induced apoptosis and inhibits invasion through down-modulation of NF-κB-regulated gene products

  • Chulwon Kim
  • Somi K. Cho
  • Ki-Dong Kim
  • Dongwoo Nam
  • Won-Seok Chung
  • Hyeung-Jin Jang
  • Seok-Geun Lee
  • Bum Sang Shim
  • Gautam SethiEmail author
  • Kwang Seok AhnEmail author
Original Paper

Abstract

We have recently reported that β-caryophyllene oxide (CPO) can induce apoptosis, suppress tumor growth, and inhibit metastasis through the suppression of signal transducer and activator of transcription 3, PI3K/AKT/mTOR/S6K1 signaling cascades and ROS-mediated MAPKs activation. In the present study, we found that CPO potentiated the apoptosis induced by tumor necrosis factor α (TNFα) and chemotherapeutic agents, suppressed TNFα-induced tumor cell invasion, all of which are known to require NF-κB activation. We found that TNFα stimulated the expression of gene products involved in anti-apoptosis (IAP1, IAP2, Bcl-2, Bcl-xL, and survivin), proliferation (COX-2, cyclin D1, and c-Myc), invasion (MMP 9 and ICAM-1), and angiogenesis (VEGF) and that CPO treatment suppressed their expression. Because these gene products are also regulated by proinflammatory transcription factor NF-κB, we postulated that CPO may mediate its effects by modulating the NF-κB pathway. We found that CPO blocked both inducible and constitutive NF-κB activation in a wide variety of tumor cells. CPO was also found to inhibit the TNFα-induced degradation of IκBα through the inhibition of activation of IκBα kinase and p65 nuclear translocation and phosphorylation. Interestingly, CPO failed to potentiate the apoptotic effect induced by TNFα in p65 −/− cells as compared to the wild-type. Thus, overall, our results indicate that the inhibition of NF-κB is one of major mechanisms by which CPO enhances TNFα-induced apoptosis and suppresses invasion.

Keywords

β-Caryophyllene oxide NF-κB, TNFα Apoptosis 

Notes

Acknowledgments

This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean Ministry of Education, Science and Technology (MoEST) (No. 2011-0006220).

Conflict of interest

The authors have no conflicts of interest to disclosure.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Chulwon Kim
    • 1
  • Somi K. Cho
    • 2
  • Ki-Dong Kim
    • 1
  • Dongwoo Nam
    • 1
  • Won-Seok Chung
    • 1
  • Hyeung-Jin Jang
    • 1
  • Seok-Geun Lee
    • 1
  • Bum Sang Shim
    • 1
  • Gautam Sethi
    • 3
    Email author
  • Kwang Seok Ahn
    • 4
    Email author
  1. 1.College of Korean MedicineKyung Hee UniversitySeoulRepublic of Korea
  2. 2.Faculty of Biotechnology, College of Applied Life Sciences, and Subtropical Horticulture Research InstituteJeju National UniversityChejuRepublic of Korea
  3. 3.Department of Pharmacology, Yong Loo Lin School of Medicine, and Cancer Science Institute of SingaporeNational University of SingaporeSingaporeSingapore
  4. 4.Department of Korean Pathology, College of Korean MedicineKyung Hee UniversitySeoulRepublic of Korea

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