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Cacalol, a natural sesquiterpene, induces apoptosis in breast cancer cells by modulating Akt-SREBP-FAS signaling pathway

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Abstract

We previously isolated cacalol as a free radical-scavenging compound from Cacalia delphiniifolia which is a traditional Asian herbal plant and is believed to have medicinal effects on cancer. In this report, we demonstrated that cacalol has strong anti-proliferation effect on breast cancer cells and induces apoptosis by activating a pro-apoptotic pathway. We also found that a combination of cacalol and other chemotherapeutic drugs (Taxol and cyclophosphamide) synergistically induced apoptosis and partially overcame chemo-resistance. To further gain a mechanistic insight, we tested a potential inhibitory effect of cacalol on fatty acid synthase gene (FAS) in breast cancer cells, and found that cacalol significantly modulated the expression of the FAS gene, which resulted in apoptosis through activation of DAPK2 and caspase 3. We have also shown that cacalol significantly suppressed the Akt-sterol regulatory element-binding proteins (SREBP) signaling pathway and concomitant transcriptional activation of FAS. In a xenograft model of nude mouse, when cacalol was administered intraperitoneally, tumor growth was significantly suppressed. Importantly, oral administration of cacalol before implanting tumors showed significant preventive effect on tumor growth in the same animal model. Furthermore, the treatment of mice with a combination of low dose of Taxol and cacalol significantly suppressed the tumor growth. Taken together, our results indicate that cacalol induces apoptosis in breast cancer cells and impairs mammary tumor growth in vivo by blocking the expression of the FAS gene through modulation of Akt-SREBP pathway, suggesting that cacalol has potential utility as a chemopreventive and chemotherapeutic agent for breast cancer.

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Abbreviations

FAS:

Fatty acid synthase.

ROS:

Reactive oxygen species.

SREBP:

Sterol regulatory element-binding protein

CPA:

Cyclophosphamide

HIF1:

Hypoxia-inducible factor-1

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Authors and Affiliations

  1. Department of Medical Microbiology, Immunology & Cell Biology, Southern Illinois University School of Medicine, 801 N. Rutledge St., P. O. Box 19626, Springfield, IL, 62794-9626, USA

    Wen Liu, Eiji Furuta, Misako Watabe, Fei Xing, Puspa R. Pandey, Hiroshi Okuda, Sudha K. Pai, Deliang Cao, Yin-Yuan Mo, Aya Kobayashi, Megumi Iiizumi, Koji Fukuda, Bo Xia & Kounosuke Watabe

  2. Department of Food and Nutrition, Japan Women’s University, Tokyo, Japan

    Kazutoshi Shindo

  3. Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA

    Laura L. Murphy

Authors
  1. Wen Liu
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  2. Eiji Furuta
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  3. Kazutoshi Shindo
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  4. Misako Watabe
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  15. Bo Xia
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  16. Kounosuke Watabe
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Correspondence to Kounosuke Watabe.

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Liu, W., Furuta, E., Shindo, K. et al. Cacalol, a natural sesquiterpene, induces apoptosis in breast cancer cells by modulating Akt-SREBP-FAS signaling pathway. Breast Cancer Res Treat 128, 57–68 (2011). https://doi.org/10.1007/s10549-010-1076-8

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  • DOI: https://doi.org/10.1007/s10549-010-1076-8

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