Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy.
Cells. 2023 Jul 20;12(14):1895. doi: 10.3390/cells12141895.
APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through the control of gene expression by a redox-based mechanism. APE1 is overexpressed and serum-secreted in different cancers, representing a prognostic and predictive factor and a promising non-invasive biomarker. Strategies directly targeting APE1 functions led to the identification of inhibitors showing potential therapeutic value, some of which are currently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism that are still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating onco-miRNA maturation, and oxidized RNA decay. Recent data point out a control role for APE1 in the expression and sorting of onco-miRNAs within secreted extracellular vesicles. This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy emerging from the unexpected finding of the APE1 role in miRNA processing for personalized therapy.
APE1 是碱基切除修复途径中必不可少的内切核酸酶，可维持基因组稳定性。通过氧化还原机制控制基因表达，它被鉴定为促进肿瘤进展和化疗耐药的关键因素。APE1 在不同癌症中过度表达并分泌到血清中，是一种预后和预测因素，也是一种很有前途的非侵入性生物标志物。直接针对 APE1 功能的策略导致了抑制剂的鉴定，这些抑制剂显示出潜在的治疗价值，其中一些目前正在临床试验中。有趣的是，有证据表明 APE1 在 RNA 代谢中具有新的作用，这些作用尚不完全清楚，包括其在化学抗性表型中处理受损 RNA、调节致癌 miRNA 成熟和氧化 RNA 降解的活性。最近的数据指出，APE1 在细胞外囊泡中分泌的癌 miRNA 的表达和分选中具有控制作用。这篇综述集中讨论了过去二十年研究的优缺点，这些研究旨在鉴定 APE1 的氧化还原或 DNA 修复功能的抑制剂，以定义针对癌症的新型靶向治疗。我们将讨论从 miRNA 处理中发现 APE1 作用的意外发现中为个性化治疗带来的癌症治疗新视角。
