Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, 200092, Shanghai, China.
Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, 200092, Shanghai, China.
Chem Biol Interact. 2024 Aug 25;399:111149. doi: 10.1016/j.cbi.2024.111149. Epub 2024 Jul 18.
Rhabdomyosarcoma (RMS) represents one of the most lethal soft-tissue sarcomas in children. The toxic trace element arsenic has been reported to function as a radiosensitizer in sarcomas. To investigate the role of arsenic sulfide (AsS) in enhancing radiation sensitization in RMS, this study was conducted to elucidate its underlying mechanism in radiotherapy. The combination of AsS and radiotherapy showed significant inhibition in RMS cells, as demonstrated by the cell counting kit-8 (CCK-8) assay and flow cytometry. Subsequently, we demonstrated for the first time that AsS, as well as the knockdown of NFATc3 led to double-strand break (DSB) through increased expression of RAG1. In vivo experiment confirmed that co-treatment efficiently inhibited RMS growth. Furthermore, survival analysis of a clinical cohort consisting of 59 patients revealed a correlation between NFATc3 and RAG1 expression and overall survival (OS). Cox regression analysis also confirmed the independent prognostic significance of NFATc3 and RAG1.Taken together, AsS enhances radiosensitivity in RMS via activating NFATc3-RAG1 mediated DSB. NFATc3 and RAG1 are potential therapeutic targets. AsS will hopefully serve as a prospective radio-sensitizing agent for RMS.
横纹肌肉瘤（RMS）是儿童中最致命的软组织肉瘤之一。有毒微量元素砷已被报道在肉瘤中具有放射增敏作用。为了研究硫化砷（AsS）在增强 RMS 放射敏感性中的作用，本研究旨在阐明其在放射治疗中的潜在机制。AsS 与放射治疗的联合应用在 RMS 细胞中表现出显著的抑制作用，这一点通过细胞计数试剂盒-8（CCK-8）检测和流式细胞术得到了证实。随后，我们首次证明，AsS 以及 NFATc3 的敲低通过增加 RAG1 的表达导致双链断裂（DSB）。体内实验证实了联合治疗能有效抑制 RMS 的生长。此外，对包含 59 名患者的临床队列的生存分析表明，NFATc3 和 RAG1 的表达与总生存期（OS）之间存在相关性。Cox 回归分析也证实了 NFATc3 和 RAG1 的独立预后意义。综上所述，AsS 通过激活 NFATc3-RAG1 介导的 DSB 增强 RMS 的放射敏感性。NFATc3 和 RAG1 是潜在的治疗靶点。AsS 有望成为 RMS 的一种有前途的放射增敏剂。
