RESUMO
The biochemical mechanisms that underlie hypoxia-induced NF-kappaB activity have remained largely undefined. Here, we find that prolonged hypoxia-induced NF-kappaB activation is restricted to cancer cell lines infected with high-risk human papillomavirus (HPV) serotypes. The HPV-encoded E6 protein is necessary and sufficient for prolonged hypoxia-induced NF-kappaB activation in these systems. The molecular target of E6 in the NF-kappaB pathway is the CYLD lysine 63 (K63) deubiquitinase, a negative regulator of the NF-kappaB pathway. Specifically, hypoxia stimulates E6-mediated ubiquitination and proteasomal degradation of CYLD. Given the established role of NF-kappaB in human carcinogenesis, these findings provide a potential molecular/viral link between hypoxia and the adverse clinical outcomes observed in HPV-associated malignancies.
Assuntos
Hipóxia Celular , NF-kappa B/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Supressoras de Tumor/fisiologia , Animais , Adesão Celular , Células Cultivadas , Enzima Desubiquitinante CYLD , Ensaio de Desvio de Mobilidade Eletroforética , Células Epidérmicas , Epiderme/metabolismo , Epiderme/virologia , Feminino , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Queratinócitos/virologia , Luciferases/metabolismo , Camundongos , Camundongos Nus , NF-kappa B/genética , Proteínas Oncogênicas Virais/genética , Oxigênio/metabolismo , Papillomaviridae/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Proteínas Repressoras/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Proteínas Supressoras de Tumor/antagonistas & inibidores , Ubiquitina/metabolismo , UbiquitinaçãoRESUMO
Constitutive nuclear factor-kappaB (NF-kappaB) 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-kappaB 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-kappaB 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-kappaB 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-kappaB activity.
