Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression.
Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression.
复制标题
靶向 DNA Flap 核酸内切酶 1 阻止乳腺癌进展
DOI：
10.1016/j.ebiom.2016.11.012
复制
发表时间：
2016-12
期刊：
影响因子：
11.1
通讯作者：
Guo, Zhigang
中科院分区：
文献类型：
--
作者：
He, Lingfeng;Zhang, Yilan;Sun, Hongfang;Jiang, Feng;Yang, Huan;Wu, Huan;Zhou, Ting;Hu, Sencai;Kathera, Chandra Sekhar;Wang, Xiaojun;Chen, Haoyan;Li, Hongzhi;Shen, Binghui;Zhu, Yongqiang;Guo, Zhigang
关键词：
DNA瓣状核酸内切酶1（FEN 1）通过参与DNA复制和修复，在维持基因组稳定性和完整性方面起着关键作用。细胞中FEN 1的抑制导致DNA复制的延迟和未修复的DNA中间体的积累，导致DNA双链断裂（DSB）和细胞凋亡。因此，靶向FEN 1可以作为癌症治疗的有效策略。在这项研究中，我们证明了FEN 1在乳腺癌中过表达，并且对癌细胞的快速增殖至关重要。我们发现，操纵细胞中的FEN 1水平改变了癌细胞对化疗药物的反应。此外，我们发现了一种小分子化合物SC 13，它特异性地抑制FEN 1活性，从而干扰体外和细胞中的DNA复制和修复。SC 13抑制癌细胞增殖并诱导细胞中的染色体不稳定性和细胞毒性。重要的是，SC 13使癌细胞对DNA损伤诱导治疗方式敏感，并在小鼠模型中阻止癌症进展。这些发现可以为乳腺癌和其他癌症的治疗建立一个范例。FEN 1在癌细胞中过表达，对癌细胞生长至关重要; FEN 1的下调导致细胞生长迟缓，并使癌细胞对化疗药物敏感; SC 13，一种FEN 1特异性抑制剂，在体外和异种移植肿瘤小鼠中抑制癌症生长。当今临床上使用的大多数抗癌药物都是通过干扰DNA复制或诱导DNA损伤来杀死细胞，从而导致细胞凋亡。然而，癌细胞已经进化出一套高效的DNA复制和修复系统，以满足癌细胞快速分裂的需要，并保护DNA免受内源性和外源性DNA损伤。FEN 1已被证明是DNA复制和修复途径中的重要因素，使FEN 1成为开发抗癌药物的逻辑靶标，作为治疗依赖其活性的癌症的独立药物，以及作为与导致DNA损伤的化疗药物组合的疗法。
DNA flap endonuclease 1 (FEN1) plays critical roles in maintaining genome stability and integrity by participating in both DNA replication and repair. Suppression of FEN1 in cells leads to the retardation of DNA replication and accumulation of unrepaired DNA intermediates, resulting in DNA double strand breaks (DSBs) and apoptosis. Therefore, targeting FEN1 could serve as a potent strategy for cancer therapy. In this study, we demonstrated that FEN1 is overexpressed in breast cancers and is essential for rapid proliferation of cancer cells. We showed that manipulating FEN1 levels in cells alters the response of cancer cells to chemotherapeutic drugs. Furthermore, we identified a small molecular compound, SC13 that specifically inhibits FEN1 activity, thereby interfering with DNA replication and repair in vitro and in cells. SC13 suppresses cancer cell proliferation and induces chromosome instability and cytotoxicity in cells. Importantly, SC13 sensitizes cancer cells to DNA damage-inducing therapeutic modalities and impedes cancer progression in a mouse model. These findings could establish a paradigm for the treatment of breast cancer and other cancers as well. FEN1 is overexpressed in cancer cells and essential for cancer cell growth; Down regulation of FEN1 leads to retarded cell growth and sensitizes cancer cells to chemotherapeutic agents; SC13, a FEN1 specific inhibitor, inhibits cancer growth in vitro and in xenograft tumor mice. Most anticancer agents used in clinic today kill cells by interfering DNA replication or inducing DNA damage, which in turn lead to cell apoptosis. However, cancer cells have evolved a compilation of highly effective DNA replication and repair systems to meet up the requirement of rapidly dividing of cancer cells and protect DNA against both endogenous and exogenous DNA damage. FEN1 has been shown to be an important factor in both DNA replication and repair pathways, making FEN1 a logical target for developing anticancer drugs as stand-alone agents for treating cancers that rely on its activity and as a therapy in combination with chemotherapeutic agents that cause DNA damage.
登录
查看更多内容
影响因子：
5.3
作者：
Guo, Zhigang;Qian, Limin;Shen, Binghui
通讯作者：
Shen, Binghui
影响因子：
28.2
作者：
Bose R;Kavuri SM;Searleman AC;Shen W;Shen D;Koboldt DC;Monsey J;Goel N;Aronson AB;Li S;Ma CX;Ding L;Mardis ER;Ellis MJ
通讯作者：
Ellis MJ
影响因子：
4.8
作者：
Kao, KI;Henricksen, LA;Bambara, RA
通讯作者：
Bambara, RA
DOI：
10.1073/pnas.202427399
发表时间：
2002-10-01
影响因子：
11.1
作者：
Laio, A;Parrinello, M
通讯作者：
Parrinello, M
影响因子：
3.7
作者：
Jaiswal AS;Banerjee S;Aneja R;Sarkar FH;Ostrov DA;Narayan S
通讯作者：
Narayan S