Abstract
Abstract Purpose: Sphingosine kinase 1 (SK1) is over-expressed in various human cancers with pro-growth effects and its inhibitors has been suggested potential anti-cancer agents. This study was designed to investigate the therapeutic potential of SK1 inhibitor in epithelial ovarian carcinoma (EOC). Experimental design: The expression of SK1 protein was evaluated using immunohistochemistry in patients with EOC. EOC cell lines (A2780, SKOV3ip1, A2780-CP20, SKOV3-TR, ES2 and RMG2) were used in this study to test SK1 siRNA or inhibitors. We used two kinds of SK inhibitor including SK inhibitor (for both SK1 and 2) and FTY720 (specifically inhibiting SK1) to check cell proliferation, apoptosis, angiogenesis and invasion using MTT, FACS, ELISA and wound-healing assay, respectively. Furthermore, in vivo experiments were performed to test the FTY720 on tumor growth in orthotopic EOC mouse model. Results: The expression of SK1 protein in primary EOC tissues was strongly observed in all of patients; however, there was no expression of SK1 protein in the normal ovarian epithelium (n=5). Blocking SK1 by its siRNA or inhibitors significantly affected cell proliferation, apoptosis, angiogenesis and invasion in A2780-PAR and SKOV3ip1 cells. SK1 inhibitors led to decrease of SK enzymatic activity in cells. Furthermore, utilizing the in vivo animal model (A2780-PAR), FTY720 treatment significantly decreased the total tumor weight compared with control (P < 0.05). Conclusions: These results show that therapeutic targeting of SK1 with its inhibitor could have potentials of novel therapeutics for EOC. Citation Format: Jeong-Won Lee, Ji Yoon Ryu, Hye-Kyung Jeon, Young-Ae Park, Young-Jae Cho, Jung-Joo Choi, Yoo-Young Lee, Tae-Joong Kim, Chel Hun Choi, Byoung-Gie Kim, Duk-Soo Bae. Therapeutic targeting for sphingosine kinase 1 in epithelial ovarian cancer. [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 4618. doi:10.1158/1538-7445.AM2014-4618
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