Abstract
BackgroundNuclear 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 FindingsIn 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/ SignificanceOur 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.
Highlights
Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in men worldwide [1]
We provide the first evidence that the saponin a-tomatine can efficiently inhibit the growth of prostate cancer tumors in vivo without inducing overt toxicity
Our analysis of recovered mouse tumors suggest that mechanistically a-tomatine mediates its antiprostate cancer effects in vivo by blocking, at least in part, the proliferative and anti-apoptotic effects of nuclear factor-kappa B (NF-kB) signaling by reducing translocation of this protein complex to the nucleus
Summary
Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in men worldwide [1] As progression of this malignancy is dependent on the androgen receptor, therapies that target activating ligands (the hormones testosterone and dihydrotestosterone) produce response rates in patients of up to 95% [2]. Various stimuli, including tumor necrosis-alpha (TNF-a), phorbol ester and lipopolysaccharides (LPS), result in IkBa kinase activation, which mediates IkBa phosphorylation at Ser and Ser followed by its ubiquitination and proteasome-mediated degradation This releases the NF-kB p50/p65 heterodimer, which translocates to the nucleus, where it binds to consensus sequence motifs to induce gene transcription. Our previous study reported the pro-apoptotic effect of a-tomatine against androgen-independent human prostatic adenocarcinoma PC-3 cells through the inhibition of TNF-a-induced NF-kB nuclear translocation [18]. This study demonstrates the potent anti-tumor activity of a-tomatine against human androgenindependent prostate cancer in vivo
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