Lee Jeong-Won, Ryu Ji-Yoon, Yoon Gun, Jeon Hye-Kyung, Cho Young-Jae, Choi Jung-Joo, Song Sang Yong, Do In-Gu, Lee Yoo-Young, Kim Tae-Joong, Choi Chel Hun, Kim Byoung-Gie, Bae Duk-Soo
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Int J Cancer. 2015 Jul 1;137(1):221-9. doi: 10.1002/ijc.29362. Epub 2014 Dec 8.
Sphingosine kinase 1 (SK1) is over-expressed in multiple types of human cancer. SK1 has growth-promoting effects and has been proposed as a potential therapeutic target. We investigated the therapeutic effects of SK1 inhibition in epithelial ovarian carcinoma (EOC). SK1 siRNA or inhibitors were tested in EOC cell lines, including A2780, SKOV3ip1, A2780-CP20, SKOV3-TR, ES2 and RMG2. Cells were treated with SK inhibitor or FTY720, and cell proliferation, apoptosis, angiogenesis and invasion were examined by MTT, FACS, ELISA and wound-healing assays, respectively. In vivo experiments were performed to test the effects of FTY720 on tumor growth in orthotopic mouse xenografts of EOC cell lines A2780 or SKOV3ip1 and a patient-derived xenograft (PDX) model of clear cell ovarian carcinoma (CCC). Blocking SK1 with siRNA or inhibitors significantly reduced proliferation, angiogenesis and invasion, and increased apoptosis in chemosensitive (A2780 and SKOV3ip1) and chemoresistant (A2780-CP20, SKOV3-TR, ES2 and RMG2) EOC cells. SK1 inhibitors also decreased the intracellular enzymatic activity of SK1. Furthermore, FTY720 treatment significantly decreased the in vivo tumor weight in xenograft models of established cell lines (A2780 and SKOV3ip1) and a PDX model for CCC compared to control (p < 0.05). These results support therapeutic targeting of SK1 as a potential new strategy for EOC.
鞘氨醇激酶1（SK1）在多种人类癌症中过度表达。SK1具有促进生长的作用，并已被提议作为潜在的治疗靶点。我们研究了抑制SK1对上皮性卵巢癌（EOC）的治疗效果。在EOC细胞系中测试了SK1 siRNA或抑制剂，包括A2780、SKOV3ip1、A2780-CP20、SKOV3-TR、ES2和RMG2。用SK抑制剂或FTY720处理细胞，分别通过MTT、FACS、ELISA和伤口愈合试验检测细胞增殖、凋亡、血管生成和侵袭。进行体内实验以测试FTY720对EOC细胞系A2780或SKOV3ip1原位小鼠异种移植瘤以及透明细胞卵巢癌（CCC）患者来源异种移植（PDX）模型中肿瘤生长的影响。用siRNA或抑制剂阻断SK1可显著降低化疗敏感（A2780和SKOV3ip1）和化疗耐药（A2780-CP20、SKOV3-TR、ES2和RMG2）的EOC细胞的增殖、血管生成和侵袭，并增加凋亡。SK1抑制剂还降低了SK1的细胞内酶活性。此外，与对照组相比，FTY720治疗显著降低了已建立细胞系（A2780和SKOV3ip1）异种移植模型以及CCC的PDX模型中的体内肿瘤重量（p < 0.05）。这些结果支持将SK1作为EOC潜在新治疗策略的治疗靶点。
