文章：

抑制DHODH增强复制相关基因组不稳定性并促进子宫内膜癌敏感性

Inhibition of DHODH Enhances Replication-Associated Genomic Instability and Promotes Sensitivity in Endometrial Cancer

原文发布日期：6 December 2023

DOI: 10.3390/cancers15245727

类型: Article

开放获取: 是

英文摘要：

Endometrial carcinoma (EC) is the most common gynecological malignancy in the United States. De novo pyrimidine synthesis pathways generate nucleotides that are required for DNA synthesis. Approximately 38% of human endometrial tumors present with an overexpression of human dihydroorotate dehydrogenase (DHODH). However, the role of DHODH in cancer cell DNA replication and its impact on modulating a treatment response is currently unknown. Here, we report that endometrial tumors with overexpression of DHODH are associated with a high mutation count and chromosomal instability. Furthermore, tumors with an overexpression of DHODH show significant co-occurrence with mutations in DNA replication polymerases, which result in a histologically high-grade endometrial tumor. An in vitro experiment demonstrated that the inhibition of DHODH in endometrial cancer cell lines significantly induced replication-associated DNA damage and hindered replication fork progression. Furthermore, endometrial cancer cells were sensitive to the DHODH inhibitor either alone or in combination with the Poly (ADP-ribose) polymerase 1 inhibitor. Our findings may have important clinical implications for utilizing DHODH as a potential target to enhance cytotoxicity in high-grade endometrial tumors.

摘要翻译： 

子宫内膜癌是美国最常见的妇科恶性肿瘤。从头嘧啶合成途径产生DNA合成所需的核苷酸。约38%的人类子宫内膜肿瘤存在人二氢乳清酸脱氢酶过度表达。然而，DHODH在癌细胞DNA复制中的作用及其对治疗反应调节的影响目前尚不清楚。本研究发现DHODH过度表达的子宫内膜肿瘤与高突变负荷和染色体不稳定性相关。此外，DHODH过度表达的肿瘤与DNA复制聚合酶突变显著共存，导致组织学高级别子宫内膜癌的发生。体外实验表明，抑制子宫内膜癌细胞系中的DHODH可显著诱导复制相关DNA损伤并阻碍复制叉进展。值得注意的是，子宫内膜癌细胞对DHODH抑制剂单药或联合聚腺苷二磷酸核糖聚合酶1抑制剂治疗均表现出敏感性。这些发现可能为利用DHODH作为潜在靶点增强高级别子宫内膜肿瘤的细胞毒性提供重要临床启示。

原文链接：

Inhibition of DHODH Enhances Replication-Associated Genomic Instability and Promotes Sensitivity in Endometrial Cancer