Constitutive nuclear factor-KB (NF-KB) activation is observed in androgen-independent prostate cancer and represents a predictor for biochemical recurrence after radical prostatectomy. Dietary agents such as pomegranate extract (PE) have received increasing attention as potential agents to prevent the onset or progression of many malignancies, including prostate cancer. Here, we show that PE inhibited NF-KB and cell viability of prostate cancer cell lines in a dose-dependent fashion in vitro. Importantly, maximal PE-induced apoptosis was dependent on PE-mediated NF-KB blockade. In the LAPC4 xenograft model, PE delayed the emergence of LAPC4 androgen-independent xenografts in castrated mice through an inhibition of proliferation and induction of apoptosis. Moreover, the observed increase in NF-KB activity during the transition from androgen dependence to androgen independence in the LAPC4 xenograft model was abrogated by PE. Our study represents the first description of PE as a promising dietary agent for the prevention of the emergence of androgen independence that is driven in part by heightened NF-KB activity. [Mol Cancer Ther 2008;7(9):2662 -71]
SUMMARY The biochemical mechanisms that underlie hypoxia-induced NF-κB activity have remained largely undefined. We found that prolonged hypoxia-induced NF-κB activation is restricted to cancer cell lines infected with high risk human papilloma virus (HPV) serotypes. The HPV-encoded E6 protein is necessary and sufficient for prolonged hypoxia-induced NF-κB activation in these systems. The molecular target of E6 in the NF-κB pathway is the CYLD lysine 63 (K63) deubiquitinase, a negative regulator of the NF-κB pathway. Specifically, hypoxia stimulates E6-mediated ubiquitination and proteasomal degradation of CYLD. Given the established role of NF-κB in human carcinogenesis, these findings provide a potential molecular/viral link between hypoxia and the adverse clinical outcomes observed in HPV-associated malignancies. SIGNIFICANCE Intratumoral hypoxia is a critical factor in the poor clinical outcomes of human malignancies, most notably cervix and head and neck cancers. We found that prolonged hypoxia-induced NF-κB activation is not a generalized phenomenon amongst cancer cells but rather is restricted to human papilloma (HPV)-positive cancers, such as cervix and head and neck cancers. Under hypoxic conditions, the HPV-encoded E6 protein inactivates the CYLD tumor suppressor, a negative regulator of the NF-κB pathway and thereby allows for unrestricted activation of NF-κB. Because NF-κB-induced genes promote survival, proliferation, and angiogenesis, our findings illustrate how a common human virus adapts to hypoxia and helps account for the aggressive tumor biology associated with hypoxia.
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