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
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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science
2013
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| Online Access: | http://eprints.um.edu.my/8249/1/Lee-2013-Alpha-Tomatine_Atten.pdf |
| _version_ | 1825719510478356480 |
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| author | Lee, S.T. Wong, P.F. He, H. Hooper, J.D. Mustafa, Mohd Rais |
| author_facet | Lee, S.T. Wong, P.F. He, H. Hooper, J.D. Mustafa, Mohd Rais |
| author_sort | Lee, S.T. |
| collection | UM |
| description | 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. |
| first_indexed | 2024-03-06T05:20:51Z |
| format | Article |
| id | um.eprints-8249 |
| institution | Universiti Malaya |
| language | English |
| last_indexed | 2024-03-06T05:20:51Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | um.eprints-82492019-12-18T06:44:52Z http://eprints.um.edu.my/8249/ 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, Mohd Rais R Medicine 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. Public Library of Science 2013 Article PeerReviewed application/pdf en http://eprints.um.edu.my/8249/1/Lee-2013-Alpha-Tomatine_Atten.pdf 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 <https://doi.org/10.1371/journal.pone.0057708>. 10.1371/journal.pone.0057708 |
| spellingShingle | R Medicine Lee, S.T. Wong, P.F. He, H. Hooper, J.D. Mustafa, Mohd Rais 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | R Medicine |
| url | http://eprints.um.edu.my/8249/1/Lee-2013-Alpha-Tomatine_Atten.pdf |
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