Triple-negative breast cancer (TNBC) accounts for approximately 10–20% of all breast cancers and is one of the leading causes of mortality among females. Radiotherapy is essential during the treatment of breast cancer. Growing evidence has indicated that peptidyl arginine deiminase-4 (PAD4) inhibitor can alleviate the development of multiple cancers, including breast cancer, through inhibiting cell proliferation. GSK484 is considered to be a highly potent PAD4-selective inhibitors. However, the potential role and mechanism of GSK484 in TNBC remain unclear. In this study, we intended to explore the effects of GSK484 on the radiosensitivity of TNBC cell lines (MDA-MB-231 and BT-549). We found that the pretreatment of GSK484 enhanced irradiation (IR)-induced inhibitory effects on cell proliferation, migration and invasion. Besides, our findings revealed that GSK484 facilitated TNBC cell apoptosis. IR treatment-induced increase of the protein level of ATG5 and ATG7, and decrease of p62 protein level were countervailed by GSK484. In addition, GSK484 enhanced DNA damage induced by IR. Moreover, in vivo experiments demonstrated that the combined treatment of IR and GSK484 showed an obvious decline of tumor growth in contrast to IR-alone or GSK484-alone treatment. Overall, GSK484 may serve as a radiosensitizer of TNBC through inhibiting IR-induced autophagy.

三阴性乳腺癌 (TNBC) 约占所有乳腺癌的 10-20%，是女性死亡的主要原因之一。在乳腺癌的治疗过程中，放疗是必不可少的。越来越多的证据表明，肽基精氨酸脱亚胺酶-4 (PAD4) 抑制剂可以通过抑制细胞增殖来缓解多种癌症的发展，包括乳腺癌。GSK484 被认为是一种高效的 PAD4 选择性抑制剂。然而，GSK484 在 TNBC 中的潜在作用和机制尚不清楚。在本研究中，我们打算探索 GSK484 对 TNBC 细胞系（MDA-MB-231 和 BT-549）放射敏感性的影响。我们发现 GSK484 的预处理增强了辐射 (IR) 诱导的对细胞增殖、迁移和侵袭的抑制作用。除了，我们的研究结果表明 GSK484 促进了 TNBC 细胞凋亡。GSK484 抵消了红外线处理诱导的 ATG5 和 ATG7 蛋白水平的增加以及 p62 蛋白水平的降低。此外，GSK484 增强了 IR 诱导的 DNA 损伤。此外，体内实验表明，与单独使用 IR 或单独使用 GSK484 治疗相比，IR 和 GSK484 的联合治疗显示出肿瘤生长的明显下降。总的来说，GSK484 可以通过抑制 IR 诱导的自噬作为 TNBC 的放射增敏剂。体内实验表明，与单独使用 IR 或单独使用 GSK484 治疗相比，IR 和 GSK484 的联合治疗显示肿瘤生长明显下降。总的来说，GSK484 可以通过抑制 IR 诱导的自噬作为 TNBC 的放射增敏剂。体内实验表明，与单独使用 IR 或单独使用 GSK484 治疗相比，IR 和 GSK484 的联合治疗显示肿瘤生长明显下降。总的来说，GSK484 可以通过抑制 IR 诱导的自噬作为 TNBC 的放射增敏剂。