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

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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.

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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).

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The authors have no conflicts of interest to disclosure.

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Authors and Affiliations

  1. College of Korean Medicine, Kyung Hee University, 1 Hoegi-dong Dongdaemungu, Seoul, 130-701, Republic of Korea

    Chulwon Kim, Ki-Dong Kim, Dongwoo Nam, Won-Seok Chung, Hyeung-Jin Jang, Seok-Geun Lee & Bum Sang Shim

  2. Faculty of Biotechnology, College of Applied Life Sciences, and Subtropical Horticulture Research Institute, Jeju National University, Cheju, 690-756, Republic of Korea

    Somi K. Cho

  3. Department of Pharmacology, Yong Loo Lin School of Medicine, and Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117597, Singapore

    Gautam Sethi

  4. Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, 1 Hoegi-Dong Dongdaemun-Gu, Seoul, 130-701, Republic of Korea

    Kwang Seok Ahn

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  1. Chulwon Kim
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  2. Somi K. Cho
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Correspondence to Gautam Sethi or Kwang Seok Ahn.

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Chulwon Kim and Somi K. Cho have contributed equally to this study.

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Kim, C., Cho, S.K., Kim, KD. et al. β-Caryophyllene oxide potentiates TNFα-induced apoptosis and inhibits invasion through down-modulation of NF-κB-regulated gene products. Apoptosis 19, 708–718 (2014). https://doi.org/10.1007/s10495-013-0957-9

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  • DOI: https://doi.org/10.1007/s10495-013-0957-9

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