International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Department of Biology and Genetics, Hai Phong University of Medicine and Pharmacy, Hai Phong 180000, Vietnam.
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Neoplasia. 2024 Dec;58:101075. doi: 10.1016/j.neo.2024.101075. Epub 2024 Oct 21.
Atypical teratoid rhabdoid tumor (ATRT) is an aggressive brain tumor that mainly affects young children. Our recent study reported a promising therapeutic strategy to trigger DNA damage, impede homologous recombination repair, and induce apoptosis in ATRT cells by targeting ribonucleotide reductase regulatory subunit M2 (RRM2). COH29, an inhibitor of RRM2, effectively reduced tumor growth and prolonged survival in vivo. Herein, we explored the underlying mechanisms controlling these functions to improve the clinical applicability of COH29 in ATRT.
Molecular profiling of ATRT patients and COH29-treated cells was analyzed to identify the specific signaling pathways, followed by validation using a knockdown system, flow cytometry, q-PCR, and western blot.
Elevated E2F1 and its signaling pathway were correlated with poor prognosis. RRM2 inhibition induced DNA damage and activated ATM, which reduced Rb phosphorylation to promote Rb-E2F1 interaction and hindered E2F1 functions. E2F1 activity suppression led to decreased E2F1-dependent target expressions, causing cell cycle arrest in the G1 phase, decreased S phase cells, and blocked DNA damage repair.
Our study highlights the role of ATM/Rb/E2F1 pathway in controlling cell cycle arrest and apoptosis in response to RRM2 inhibition-induced DNA damage. This provides insight into the therapeutic benefits of COH29 and suggests targeting this pathway as a potential treatment for ATRT.
胚胎性横纹肌样瘤（ATRT）是一种侵袭性脑肿瘤，主要影响儿童。我们最近的研究报告了一种有前途的治疗策略，通过靶向核苷酸还原酶调节亚基 M2（RRM2）来触发 ATRT 细胞的 DNA 损伤、阻碍同源重组修复并诱导细胞凋亡。RRM2 的抑制剂 COH29 可有效抑制肿瘤生长并延长体内生存期。在此，我们探索了控制这些功能的潜在机制，以提高 COH29 在 ATRT 中的临床适用性。
对 ATRT 患者和 COH29 处理细胞进行分子谱分析，以确定特定的信号通路，然后使用敲低系统、流式细胞术、q-PCR 和 Western blot 进行验证。
E2F1 及其信号通路的上调与不良预后相关。RRM2 抑制诱导 DNA 损伤并激活 ATM，降低 Rb 磷酸化以促进 Rb-E2F1 相互作用并阻碍 E2F1 功能。E2F1 活性抑制导致 E2F1 依赖性靶基因表达减少，导致细胞周期停滞在 G1 期，减少 S 期细胞，并阻止 DNA 损伤修复。
本研究强调了 ATM/Rb/E2F1 通路在控制细胞周期停滞和对 RRM2 抑制诱导的 DNA 损伤的凋亡中的作用。这为 COH29 的治疗益处提供了新的见解，并表明靶向该通路是治疗 ATRT 的一种潜在方法。
