Abstract 232: Extracellular matrix components influence prostate tumor cell sensitivity to cancer-preventive agents selenium and green tea polyphenols

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Some cancer-preventive agents such as selenium and green tea polyphenols effectively prevent cancer in some cases, but fail in other cases. It could be possible that the cancer-preventive actions of these agents may be altered by the interaction of cancer cells with the extracellular matrix (ECM) components, thus making this an important issue to study. Others have previously cloned a family of human prostate cancer cell lines with a common lineage that show the progression of characteristics from low to high degrees of malignancy and mimic different stages of tumor progression seen in human prostate cancer. For this study, we used these prostate cancer cell lines with increasing tumorigenicity and invasive ability: WPE1-NA22 showing the lowest, WPE1-NB14 and WPE1-NB11 showing intermediate, and WPE1-NB26 showing the greatest. The low tumorigenic cell line, WPE1-NA22 resembles noninvasive prostatic intra-epithelial neoplasia and represents a good target for chemoprevention in humans. Initially, we grew these cells on the surface of ECM components, laminin, collagen I, and fibronectin and determined the tumor cell sensitivity to methylseleninic acid (MSA) and epigallocatechin-3-gallate (EGCG). Poly-L-lysine was used as a control substratum. Cell growth was determined by sulforhodamine B staining assay. Then we determined whether these ECM proteins could enhance tumor cell resistance to MSA and EGCG. ECM components, but not polylysine, decreased tumor cell sensitivity to these agents. The effect of ECM components was prevented by β1 integrin-blocking antibodies suggesting that β1 integrin plays a role in mediating intracellular signaling conferring resistance against MSA and EGCG. Previously, we have shown an increase in expression of protein kinase Cϵ (PKCϵ) in advanced prostate tumor cells WPE1-NB26. A decrease in expression of PKCϵ by siRNA approach decreased the tumor cell resistance caused by ECM components. Furthermore, an inhibition of cell survival enzymes phosphoinositide-3-kinase (PI3K) with its specific inhibitor LY294002 (50 μM) as well as Akt with its specific inhibitor MK-2206 (1 μM) decreased the effect of ECM components on tumor cell survival against MSA and EGCG. WPE1-NB14, a low tumorigenic cell line having low PKCϵ and Akt activities, responded less to ECM components and showed higher sensitivity to MSA and EGCG. Conceivably, ECM components, laminin, collagen, and fibronectin induced β1 integrin signaling to activate cell survival pathways involving PKCϵ and PI3K-Akt, thereby decreasing prostate tumor cell sensitivity to MSA and EGCG. Thus, ECM may be one of the limiting factors for the action of cancer-preventive agents. Citation Format: Rayudu Gopalakrishna, Tiffany Fan, Ronald Deng, David Rayudu, Zachary W. Chen, William S. Tzeng, Usha Gundimeda. Extracellular matrix components influence prostate tumor cell sensitivity to cancer-preventive agents selenium and green tea polyphenols. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 232. doi:10.1158/1538-7445.AM2014-232