Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-kappaB-dependent mechanism.

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.

Treatment with siRNA and antisense oligonucleotides targeted to HIF-1alpha induced apoptosis in human tongue squamous cell carcinomas.

Overexpression of hypoxia inducible factor-1alpha (HIF-1alpha) in cancers has been correlated to a more aggressive tumor phenotype. We investigated the effect of HIF-1alpha knockout on the in vitro survival and death of human tongue squamous cell carcinomas (SCC-4 and SCC-9). Under normoxic condition, a basal level of HIF-1alpha protein was constitutively expressed in SCC-9 cells, albeit an undetectable level of HIF-1alpha messages. Exposure to hypoxia induced only a transient increase in mRNA transcript but a prolonged elevation of HIF-1alpha protein and its immediate downstream target gene product, VEGF. Under normoxic or hypoxic conditions, treatment of SCC-9 cells with AS-HIF-1alpha ODN suppressed both constitutive and hypoxia-induced HIF-1alpha expression at both mRNA and protein levels. Knockout of HIF-1alpha gene expression via either AS-HIF-1alpha ODN or siRNA (siRNAHIF-1alpha) treatment resulted in inhibition of cell proliferation and induced apoptosis in SCC-4 and SCC-9 cells. We also demonstrated that exposure of SCC-9 cells to hypoxia led to a time-dependent increase in the expression of bcl-2 and IAP-2, but not p53. The attenuated levels of bcl-2 and IAP-2, and the enhanced activity of caspase-3 after treatment with AS-HIF-1alpha ODN may contribute partly to the effects of HIF-1alpha blockade on SCC-9 cell death. Collectively, our data suggest that a constitutive or hypoxia-induced expression of HIF-1alpha in SCC-9 and SCC-4 cells is sufficient to confer target genes expression essential for tumor proliferation and survival. As a result, interfering with HIF-1alpha pathways by antisense or siRNA strategy may provide a therapeutic target for human tongue squamous cell carcinomas.

Correlation of Ki-67 and gelsolin expression to clinical outcome in renal clear cell carcinoma.

OBJECTIVES: To analyze the expression levels of Ki-67 and gelsolin in renal cell carcinoma (RCC) and determine their prognostic value in association with other clinicopathologic factors using tissue microarray technology. Histologic nuclear grade, performance status, and clinical stage are important prognostic factors in RCC. Because patients with tumors of similar grade, performance status, and stage may show a wide variation in biologic behavior and clinical outcome, additional biomarkers for RCC are needed to provide further prognostic information and possibly offer insight into the mechanisms of the disease. METHODS: Using a renal cancer tissue microarray, we correlated the expression of Ki-67, a marker of cell proliferation, and gelsolin, an actin-binding protein, with grade, stage, and survival in patients with clear cell RCC. RESULTS: In Cox multivariate regression analysis, stage (pT) was the most significant predictor of cancer-specific survival (P <0.0001), followed by Ki-67 (P = 0.0216). In univariate analysis, increased Ki-67 expression predicted poor cancer-specific survival (P = 0.0006) when a cutoff value for Ki-67 staining was applied. In patients with grade 2 tumors, increased Ki-67 expression and decreased gelsolin expression in the same tumor was suggestive of poor cancer-specific survival (P = 0.0507). CONCLUSIONS: Our findings support the utility of Ki-67 as a prognostic biomarker for RCC and suggest a role for gelsolin in renal carcinogenesis.