Small molecule inhibition of the CBFβ/RUNX interaction decreases ovarian cancer growth and migration through alterations in genes related to epithelial-to-mesenchymal transition.
Small molecule inhibition of the CBFβ/RUNX interaction decreases ovarian cancer growth and migration through alterations in genes related to epithelial-to-mesenchymal transition.
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DOI：
10.1016/j.ygyno.2018.03.005
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发表时间：
2018-05
影响因子：
4.7
通讯作者：
Bushweller JH
中科院分区：
文献类型：
--
作者：
Carlton AL;Illendula A;Gao Y;Llaneza DC;Boulton A;Shah A;Rajewski RA;Landen CN;Wotton D;Bushweller JH
在过去的20年里，卵巢癌的生存率和治疗改善甚微。需要新的治疗策略来对抗这种疾病。本研究探讨了化学抑制CBFβ/RUNX蛋白-蛋白相互作用对卵巢癌细胞系的影响。卵巢癌细胞系用CBFβ/RUNX抑制剂处理，并测量对增殖、DNA复制、伤口愈合和锚定非依赖性生长的影响。对化合物处理的细胞进行RNA-Seq以鉴定差异表达的基因。用SiRNA靶向化合物治疗改变的基因，并测量对DNA复制和伤口愈合的影响。化学抑制CBFβ/RUNX相互作用可降低卵巢癌细胞增殖抑制剂处理导致S期细胞周期延迟，如S期细胞百分比增加和DNA复制速率降低所示。抑制剂治疗还减少伤口愈合和锚定非依赖性生长。对化合物处理的细胞的RNA-Seq揭示了与增殖和上皮-间充质转化相关的少量基因的变化。siRNA介导的INHBA和MMP 1的敲除-两个基因的表达随着化合物处理而降低-减缓了DNA复制并损害了伤口愈合。化学抑制CBFβ/RUNX相互作用是治疗卵巢癌的可行策略。
Ovarian cancer survival and treatment have improved minimally in the past 20 years. Novel treatment strategies are needed to combat this disease. This study investigates the effects of chemical inhibition of the CBFβ/RUNX protein-protein interaction on ovarian cancer cell lines. Ovarian cancer cell lines were treated with CBFβ/RUNX inhibitors, and the effects on proliferation, DNA replication, wound healing, and anchorage-independent growth were measured. RNA-Seq was performed on compound-treated cells to identify differentially expressed genes. Genes altered by compound treatment were targeted with siRNAs, and effects on DNA replication and wound healing were measured. Chemical inhibition of the CBFβ/RUNX interaction decreases ovarian cancer cell proliferation. Inhibitor treatment leads to an S-phase cell cycle delay, as indicated by an increased percentage of cells in S-phase, and a decreased DNA replication rate. Inhibitor treatment also reduces wound healing and anchorage-independent growth. RNA-Seq on compound-treated cells revealed changes in a small number of genes related to proliferation and epithelial-to-mesenchymal transition. siRNA-mediated knockdown of INHBA and MMP1 – two genes whose expression decreases with compound treatment – slowed DNA replication and impaired wound healing. Chemical inhibition of the CBFβ/RUNX interaction is a viable strategy for the treatment of ovarian cancer.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
影响因子：
9.7
作者：
Dean M;Davis DA;Burdette JE
通讯作者：
Burdette JE
影响因子：
64.5
作者：
Mullen AC;Orlando DA;Newman JJ;Lovén J;Kumar RM;Bilodeau S;Reddy J;Guenther MG;DeKoter RP;Young RA
通讯作者：
Young RA
影响因子：
254.7
作者：
Siegel, Rebecca;Ma, Jiemin;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin