Inhibition of DHODH Enhances Replication-Associated Genomic Instability and Promotes Sensitivity in Endometrial Cancer.
Inhibition of DHODH Enhances Replication-Associated Genomic Instability and Promotes Sensitivity in Endometrial Cancer.
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抑制DHODH增强复制相关基因组不稳定性并提高子宫内膜癌的敏感性
DOI：
10.3390/cancers15245727
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发表时间：
2023-12-06
期刊：
影响因子：
5.2
通讯作者：
Kidane, Dawit
中科院分区：
文献类型：
--
作者：
Zhao, Shengyuan;Francois, Aaliyah;Kidane, Dawit
子宫内膜癌是影响女性生殖器官的最常见的癌症。超过50%的女性EC患者表现为早期、低风险的疾病，仅接受手术治疗。然而，被诊断为晚期或复发性疾病的妇女预后较差，对目前的治疗反应较差。然而，EC患者的分子机制和预后预测仍不清楚。在这项工作中，我们发现癌细胞利用失调的核苷酸代谢来促进增殖和进展。我们的目标是一个失调基因（DHODH），这对子宫内膜癌细胞的核苷酸生物合成代谢至关重要。我们的研究结果为选择子宫内膜癌患者提供了潜在的临床应用，使用“过度表达失调基因（DHODH）”作为遗传标记，使用FDA批准的药物（Teriflunomide）进行量身定制的治疗干预。此外，它还揭示了治疗“DHODH过表达”子宫内膜癌的潜在联合治疗策略（Teriflunomide+ Olaparib）。总的来说，该结果为建立未来的临床治疗干预提供了临床前数据，以提高治疗反应的有效性，提高子宫内膜癌患者的总生存期。子宫内膜癌（EC）是美国最常见的妇科恶性肿瘤。新的嘧啶合成途径产生DNA合成所需的核苷酸。大约38%的人子宫内膜肿瘤存在人二氢酸脱氢酶（DHODH）的过表达。然而，DHODH在癌细胞DNA复制中的作用及其对调节治疗反应的影响目前尚不清楚。在这里，我们报告了DHODH过表达的子宫内膜肿瘤与高突变计数和染色体不稳定性相关。此外，DHODH过表达的肿瘤与DNA复制聚合酶突变显著共存，从而导致组织学上高级别的子宫内膜肿瘤。体外实验表明，在子宫内膜癌细胞系中抑制DHODH可显著诱导复制相关的DNA损伤，并阻碍复制叉的进展。此外，子宫内膜癌细胞对DHODH抑制剂单独或与Poly （adp -核糖）聚合酶1抑制剂联合均敏感。我们的发现可能对利用DHODH作为潜在靶点来增强高级别子宫内膜肿瘤的细胞毒性具有重要的临床意义。
Endometrial cancer is the most common type of cancer that affects the female reproductive organs. Over 50% of women with EC present with early-stage, low-risk disease, and are treated with surgery alone. However, women diagnosed with advanced or recurrent disease have a poor prognosis and they have poor response to current therapies. However, the molecular mechanisms and the prognostic prediction for EC patients remain unclear. In this work, we identified that cancer cells utilize dysregulated nucleotide metabolism to enhance proliferation and progression. We targeted one of the dysregulated genes (DHODH) that is critical for metabolism of nucleotide biosynthesis in endometrial cancer cell. Our results provide potential clinical application to select endometrial cancer patient using “overexpression of dysregulated genes (DHODH) as the genetic markers for tailored therapeutic intervention using repurposed FDA approved drugs (Teriflunomide). Furthermore, it revealed a potential combination therapeutic strategy (Teriflunomide+ Olaparib) for the treatment of “DHODH overexpressing” endometrial cancer. Overall, this result provides preclinical data to establish future clinical therapeutic intervention to increase the efficacy of treatment response that improves overall survival of endometrial cancer patients. 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.
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