Alpha-tomatine attenuation of in vivo growth of subcutaneous and orthotopic xenograft tumors of human prostate carcinoma Pc-3 cells is accompanied by inactivation of nuclear factor-kappa b signaling

Lee, S.T.; Wong, P.F.; He, H.; Hooper, J.D.; Mustafa, M.R. (2013) Alpha-tomatine attenuation of in vivo growth of subcutaneous and orthotopic xenograft tumors of human prostate carcinoma Pc-3 cells is accompanied by inactivation of nuclear factor-kappa b signaling. PLoS ONE, 8 (2). e57708. ISSN 1932-6203

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    Abstract

    Background: Nuclear factor-kappa B (NF-κB) plays a role in prostate cancer and agents that suppress its activation may inhibit development or progression of this malignancy. Alpha (α)-tomatine is the major saponin present in tomato (Lycopersicon esculentum) and we have previously reported that it suppresses tumor necrosis factor-alpha (TNF-α)-induced nuclear translocation of nuclear factor-kappa B (NF-κB) in androgen-independent prostate cancer PC-3 cells and also potently induces apoptosis of these cells. However, the precise mechanism by which α-tomatine suppresses NF-κB nuclear translocation is yet to be elucidated and the anti-tumor activity of this agent in vivo has not been examined. Methodology/ Principal Findings : In the present study we show that suppression of NF-κB activation by α-tomatine occurs through inhibition of I kappa B alpha (IκBα) kinase activity, leading to sequential suppression of IκBα phosphorylation, IκBα degradation, NF-κB/p65 phosphorylation, and NF-κB p50/p65 nuclear translocation. Consistent with its ability to induce apoptosis, α-tomatine reduced TNF-α induced activation of the pro-survival mediator Akt and its inhibition of NF-κB activation was accompanied by significant reduction in the expression of NF-κB-dependent anti-apoptotic (c-IAP1, c-IAP2, Bcl-2, Bcl-xL, XIAP and survivin) proteins. We also evaluated the antitumor activity of α-tomatine against PC-3 cell tumors grown subcutaneously and orthotopically in mice. Our data indicate that intraperitoneal administration of α-tomatine significantly attenuates the growth of PC-3 cell tumors grown at both sites. Analysis of tumor material indicates that the tumor suppressing effects of α-tomatine were accompanied by increased apoptosis and lower proliferation of tumor cells as well as reduced nuclear translocation of the p50 and p65 components of NF-κB. Conclusion/ Significance: Our study provides first evidence for in vivo antitumor efficacy of α-tomatine against the human androgen-independent prostate cancer. The potential usefulness of α-tomatine in prostate cancer prevention and therapy requires further investigation.

    Item Type: Article
    Creators:
    1. Lee, S.T.
    2. Wong, P.F.
    3. He, H.
    4. Hooper, J.D.
    5. Mustafa, M.R.(Department of Pharmacology, Faculty of Medicine Building, University of Malaya, 50603 Kuala Lumpur, MALAYSIA)
    Journal or Publication Title: PLoS ONE
    Uncontrolled Keywords: Nuclear factor-kappa B (NF-κB); Alpha (α)-tomatine
    Subjects: R Medicine
    Divisions: Faculty of Medicine
    Depositing User: Ms Haslinda Lahuddin
    Date Deposited: 14 Aug 2013 08:56
    Last Modified: 04 Jul 2017 10:14
    URI: http://eprints.um.edu.my/id/eprint/8249

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