Maimon Avi, Puzzovio Pier Giorgio, Vinik Yaron, Hannuna Gavriel-David, Donzelli Sara, Rutigliano Daniela, Blandino Giovanni, Lev Sima
Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot, 76100, Israel.
Translational Oncology Research Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Redox Biol. 2025 Jul 22;86:103775. doi: 10.1016/j.redox.2025.103775.
The polynucleotide kinase/phosphatase (PNKP) is a DNA repair enzyme possessing bifunctional DNA 3'-phosphatase and DNA 5'-kinase activities. It plays an important role in the rejoining of single- and double-strand DNA breaks and is considered as a potential therapeutic target for different cancer types. Here we show that PNKP is highly expressed in triple negative breast cancer (TNBC) and associated with poor prognosis and chemoresistance. Targeting of PNKP enhanced ferroptosis in TNBC, which was associated with increased labile iron pool and ROS and concomitantly decreased in intracellular glutathione, SCD1 and GPX4 levels. Transcriptomic profiling and mechanistic data indicate that PNKP targeting robustly enhances the lysosomal and the autophagic machinery by activating STING and concurrently inhibiting STAT3, thereby increasing ferritinophagy, intracellular iron level and modulating the expression of key ferroptosis regulators. Importantly, PNKP and STAT3 are rapidly phosphorylated, colocalize, and interact upon ferroptosis induction or doxorubicin treatment, the first line treatment for TNBC patients. Targeting PNKP together with doxorubicin synergistically inhibited the growth of TNBC in an animal model and of TNBC-patients derived organoids. These results offer a promising therapeutic combination for TNBC and highlight the clinical potential of PNKP targeting and ferroptotic death for TNBC therapy.
多核苷酸激酶/磷酸酶（PNKP）是一种具有双功能DNA 3'-磷酸酶和DNA 5'-激酶活性的DNA修复酶。它在单链和双链DNA断裂的重新连接中起重要作用，被认为是不同癌症类型的潜在治疗靶点。在这里，我们表明PNKP在三阴性乳腺癌（TNBC）中高度表达，与预后不良和化疗耐药相关。靶向PNKP可增强TNBC中的铁死亡，这与不稳定铁池和活性氧增加以及细胞内谷胱甘肽、SCD1和GPX4水平同时降低有关。转录组分析和机制数据表明，靶向PNKP通过激活STING并同时抑制STAT3，有力地增强了溶酶体和自噬机制，从而增加铁自噬、细胞内铁水平并调节关键铁死亡调节因子的表达。重要的是，在铁死亡诱导或阿霉素治疗（TNBC患者的一线治疗）后，PNKP和STAT3会迅速磷酸化、共定位并相互作用。在动物模型和TNBC患者来源的类器官中，联合靶向PNKP和阿霉素可协同抑制TNBC的生长。这些结果为TNBC提供了一种有前景的治疗组合，并突出了靶向PNKP和铁死亡性死亡在TNBC治疗中的临床潜力。
