Lee, S.T. and Wong, P.F. and He, H. and Hooper, J.D. and Mustafa, Mohd Rais (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, DOI https://doi.org/10.1371/journal.pone.0057708.
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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 |
|---|---|
| Funders: | UNSPECIFIED |
| 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 00:56 |
| Last Modified: | 18 Dec 2019 06:44 |
| URI: | http://eprints.um.edu.my/id/eprint/8249 |
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