Cha Hwa Jun, Choi Jung Hye, Park In Chul, Kim Chun Ho, An Sung Kwan, Kim Tae Jin, Lee Jae Ho
Osan University, Department of Skin Care and Beauty, Osan, Gyeonggi-do 18119, Republic of Korea.
Department of Oriental Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
Int J Oncol. 2017 Apr;50(4):1279-1288. doi: 10.3892/ijo.2017.3913. Epub 2017 Mar 15.
Epithelial ovarian cancer is the most aggressive and lethal among the gynecological malignancies, which is often found disseminated to peritoneal cavity at the time of diagnosis. There is accumulating evidence on the existence of genetic alteration and amplification of fibroblast growth factor receptor (FGFR) in various cancers. Also the aberrated FGFR/FGF signaling has been implicated in cancer development and tumor microenvironment. However, the antitumor activity of BGJ398, a selective inhibitor of FGFR 1/2/3 against ovarian cancer still remains unknown. The aim of the present study is to evaluate the antitumoral activity of BGJ398 on ovarian cancer cell line SKOV3ip1 using 3-dimensional (3D) sphere culture system which has been accepted as a better mimic in vivo microenvironment than conventional 2-dimensional (2D) monolayer culture system. We examined the differential expression features of key signaling molecules which have a role in cell survival and proliferation between sphere-cultured SKOV3ip1 cells and monolayer-cultured SKOV3ip1 cells. The phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3) known as survival signaling molecules were upregulated in sphere-cultured SKOV3ip1 cells compared to in monolayer-cultured SKOV3ip1 cells. Next, we evaluated the antitumor activity of BGJ398 in monolayer-cultured SKOV3ip1 cells or sphere-cultured SKOV3ip1 cells. Treatment of BGJ398 did not affect the SKOV3ip1 cell viability in monolayer culture system, but, the cell viability of sphere-cultured SKOV3ip1 cells was markedly reduced by BGJ398. The phosphorylation of AKT and STAT3 was downregulated by BGJ398 in sphere-cultured SKOV3ip1 cells, but not in monolayer cultured-SKOV3ip1 cells. Moreover, combination treatment with BGJ398 and paclitaxel in sphere-cultured SKOV3ip1 showed synergistic inhibitory effect on cell viability. Collectively, our report reveals the BGJ398 is a potent antitumor agent against ovarian cancer and FGFR is a promising therapeutic target to anticancer therapy considering ovarian cancer metastatic microenvironment.
上皮性卵巢癌是妇科恶性肿瘤中最具侵袭性和致命性的，在诊断时往往已扩散至腹腔。越来越多的证据表明，在各种癌症中存在成纤维细胞生长因子受体（FGFR）的基因改变和扩增。此外，FGFR/FGF信号异常与癌症发展和肿瘤微环境有关。然而，FGFR 1/2/3的选择性抑制剂BGJ398对卵巢癌的抗肿瘤活性仍然未知。本研究的目的是使用三维（3D）球体培养系统评估BGJ398对卵巢癌细胞系SKOV3ip1的抗肿瘤活性，该系统已被认为比传统的二维（2D）单层培养系统更能模拟体内微环境。我们研究了在球体培养的SKOV3ip1细胞和单层培养的SKOV3ip1细胞中，对细胞存活和增殖起作用的关键信号分子的差异表达特征。与单层培养的SKOV3ip1细胞相比，在球体培养的SKOV3ip1细胞中，作为存活信号分子的AKT和信号转导及转录激活因子3（STAT3）的磷酸化上调。接下来，我们评估了BGJ398在单层培养的SKOV3ip1细胞或球体培养的SKOV3ip1细胞中的抗肿瘤活性。在单层培养系统中，BGJ398处理不影响SKOV3ip1细胞活力，但在球体培养的SKOV3ip1细胞中，BGJ398可显著降低细胞活力。在球体培养的SKOV3ip1细胞中，BGJ398可下调AKT和STAT3的磷酸化，但在单层培养的SKOV3ip1细胞中则不然。此外，在球体培养的SKOV3ip1细胞中，BGJ398与紫杉醇联合处理对细胞活力显示出协同抑制作用。总的来说，我们的报告表明BGJ398是一种有效的抗卵巢癌药物，考虑到卵巢癌转移微环境，FGFR是抗癌治疗的一个有前景的治疗靶点。
