Inhibition of FGFR2 and FGFR1 increases cisplatin sensitivity in ovarian cancer
Inhibition of FGFR2 and FGFR1 increases cisplatin sensitivity in ovarian cancer
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DOI：
10.4161/cbt.10.5.12585
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发表时间：
2010-09-01
影响因子：
3.6
通讯作者：
Jayson, Gordon C.
中科院分区：
文献类型：
--
作者：
Cole, Claire;Lau, Sin;Jayson, Gordon C.
成纤维细胞生长因子（FGF）已与恶性转化，有丝分裂发生，血管生成和化学抗性有关。这项研究的目的是确定哪些FGF和FGFR在上皮卵巢癌中起功能作用。 mRNA的限制酶分析表明，转化与从IIIC到IIIB同工型的FGFR2和FGFR3中的开关有关。在所有组织中，FGF（包括FGF7）的表达广泛，但FGF3和FGF19通过恶性细胞系和癌症组织表达，但在正常组织中不存在。使用FGFR特异性ShRNAI，我们证明FGFR2的降低在体外抑制了卵巢癌细胞系的增殖（> 50％，P <0.006）和降低顺铂IC50（> 60％，p <0.0001）。细胞周期分析表明，增加的顺铂敏感性与G（2）/M停滞和凋亡增加有关。 FGFR2 shRNAi将卵巢肿瘤异种移植物的生长速率降低了20％（P <0.006），与顺铂结合时，卵巢肿瘤异种移植物的增殖率降低了40％（p <0.007）。相比之下，RNAI诱导的FGFR1降低增加了SKOV3细胞数量，并与细胞周期的相关变化，但对ES2细胞没有影响。然而，与对照细胞相比，FGFR1 shrai在两种细胞系中降低了顺铂IC50（> 50％，p <0.0001），凋亡增加（46-50％）（35％）（p <0.004）。我们的数据一起表明，将FGFR2抑制剂与含铂的细胞毒性剂相结合以治疗上皮卵巢癌可能会增加抗肿瘤活性。但是，关于FGFR1抑制的数据表明，广泛的FGFR抑制剂可能对增殖产生意外影响。
Fibroblast Growth Factors (FGFs) have been implicated in malignant transformation, tumor mitogenesis, angiogenesis and chemoresistance. The aim of this study was to determine which FGFs and FGFRs play functional roles in epithelial ovarian cancer. Restriction enzyme analysis of mRNA revealed that transformation was associated with a switch in FGFR2 and FGFR3, from the IIIc to the IIIb isoform. There was widespread expression of FGFs, including FGF7, in all tissues but, FGF3 and FGF19 were expressed by malignant cell lines and cancer tissue but were not present in normal tissue. Using FGFR-specific shRNAi we demonstrated that reductions in FGFR2 inhibited proliferation of ovarian cancer cell lines in vitro (>50%, p < 0.006) and reduced cisplatin IC50 (>60%, p < 0.0001). Cell cycle analysis revealed increased cisplatin sensitivity was associated with increased G(2)/M arrest and increased apoptosis. FGFR2 shRNAi reduced growth rates of ovarian tumor xenografts by 20% (p < 0.006) and when combined with cisplatin caused a 40% reduction in proliferation rates (p < 0.007). In contrast, RNAi-induced reductions in FGFR1 increased SKOV3 cell numbers, with associated changes in cell cycle but had no effect on ES2 cells. However, the cisplatin IC50 was reduced (>50%, p < 0.0001) by FGFR1 shRNAi in both cell lines and there was increased apoptosis (46-50%) compared with control cells (35%) (p < 0.004). Together our data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased anti-tumor activity. However, data on the inhibition of FGFR1 suggest that broad spectrum FGFR inhibitors may have unexpected effects on proliferation.