Abstract 2904: Lyophilized black raspberry extract modulates interleukin 8 expression in human cervical cancer: An insight into phytochemical-based chemoprevention?

Introduction Cervical cancer is the 3rd most common cancer globally. The long latency from dysplasia to invasive cancer makes it amenable to prevention strategies. Phytochemicals, including those in lyophilized black raspberries (LBRs), are of great interest due to their growth inhibitory and anti-tumorigenic effects in preclinical models. Previously we showed that LBR extracts inhibited the proliferation of human cervical cancer cells in vitro in a dose- and time-dependent manner. Angiogenesis is an important part of carcinogenesis. We hypothesized that LBRs modulate the expression of an angiogenesis associated signaling cascade. Methods Human cervical cancer cells (SiHa) were treated with vehicle control (.02% DMSO) or LBR extract (200 µg/mL) for 1 or 3 days (d). Cells were harvested at 1d or 3d and RNA was extracted. Gene expression profiling was performed using a TaqMan Gene Signature Angiogenesis Array, which simultaneously screens 94 genes involved in angiogenesis. Genes demonstrating ≥2-fold change in expression following geNorm transformation were used for Ingenuity Pathway Analysis (IPA) network modeling. Biomarkers modulated in a manner favorable for cancer prevention were validated by real time RT-PCR. Results Short-term LBR exposure of SiHa cells in vitro resulted in inhibition of cell proliferation, and reduced expression of IL8 and MMP2 genes detected using the Angiogenesis Array. IPA network modeling predicted that MMP2 and NFkB would be part of the IL8 signaling cascade and this is supported in the literature. Validation with real time RT-PCR showed a 24-fold (1d) and 28-fold (3d) reduction in IL8 expression following LBR exposure. However, MMP2 and NFkB did not demonstrate a significant differential expression at either time point. Conclusion Short-term exposure of cervical cancer cells to LBR results in a striking reduction of IL8 gene expression. Although MMP2 and NFkB are associated with known IL8 signaling mechanisms, they are not modulated by LBR extract in this in vitro model. Therefore, the growth inhibitory activity and transcriptional repression of IL8 following LBR extract exposure proceed via an MMP2-NFkB-independent cascade. Other signaling mechanisms within the IL8 signaling cascade (HIF, AP1, STAT3) may be involved and will be further explored. Since IL8 plays an important role in tumor growth, metastasis, and angiogenesis, it supports the potential for phytonutrient-based chemoprevention of cervical cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2904.