RanBP2通过LRSAM1 SUMO化和泛素化稳定SLC7A1，促进铁死亡抵抗并损害肺腺癌的治疗反应
RanBP2 promotes ferroptosis resistance and compromises therapeutic response by stabilizing SLC7A1 through LRSAM1 SUMOylation and ubiquitination in lung adenocarcinoma.
作者
作者单位
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
- State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Shanghai, China. yangqing68@fudan.edu.cn.
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. yanglili@tjmuch.com.
摘要
中文
SUMO化被描述为一种泛素样翻译后修饰，与泛素化在机制上相似。重要的是，它调节一些靶蛋白的泛素化水平，从而影响蛋白质稳定性。该修饰途径的失调在各种肿瘤的发病机制和进展中起关键作用。虽然最近的研究表明蛋白质SUMO化调节肿瘤进展，但Ran结合蛋白2（RanBP2）——一种E3 SUMO连接酶——在肺腺癌（LUAD）中的具体功能和机制仍有待阐明。本研究证明RanBP2在LUAD中表达升高，并与不良预后相关。功能上，RanBP2抑制铁死亡并增强LUAD细胞的生长。机制上，RanBP2增强E3泛素连接酶富含亮氨酸重复序列和无菌α基序蛋白1（LRSAM1）的SUMO化，促进其随后在泛素-蛋白酶体途径中的降解，从而减少SLC7A11降解。稳定的SLC7A11蛋白抑制铁死亡并促进LUAD细胞生长。鉴定的RanBP2抑制剂阿莫地喹（AQ）与铁死亡诱导剂柳氮磺吡啶（SAS）联合使用，在体外和体内有效触发铁死亡并抑制LUAD细胞生长。这种组合增强了T细胞浸润并改善了抗PD-1免疫治疗疗效。该研究确定了一个新的RanBP2-LRSAM1-SLC7A11轴，促进铁死亡抵抗和LUAD进展。AQ和SAS的组合代表了LUAD的一种有前景的治疗策略。
English
SUMOylation is characterized as a ubiquitin-like post-translational modification that exhibits mechanistic similarities with ubiquitination. Importantly, it modulates the ubiquitination levels of some target proteins, thereby influencing protein stability. Dysregulation of this modification pathway plays a pivotal role in the pathogenesis and progression of various tumors. While recent studies have demonstrated that protein SUMOylation regulates tumor progression, the specific function and mechanism of Ran-binding protein 2 (RanBP2), an E3 SUMO ligase, remain to be elucidated in lung adenocarcinoma (LUAD). This study demonstrates that RanBP2 exhibits elevated expression in LUAD and correlates with poor prognosis. Functionally, RanBP2 inhibits ferroptosis and enhances the growth of LUAD cells. Mechanistically, RanBP2 augments the SUMOylation of E3 ubiquitin ligase leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1), facilitating its subsequent degradation in the ubiquitin-proteasome pathway, thereby reducing SLC7A11 degradation. The stabilized SLC7A11 protein suppresses ferroptosis and promotes LUAD cell growth. The identified RanBP2 inhibitor, amodiaquine (AQ), in combination with ferroptosis inducer sulfasalazine (SAS), effectively triggered ferroptosis and suppressed LUAD cell growth in vitro and in vivo. This combination enhanced T-cell infiltration and improved anti-PD-1 immunotherapy efficacy. The research identifies a novel RanBP2-LRSAM1-SLC7A11 axis that promotes ferroptosis resistance and LUAD progression. The combination of AQ and SAS represents a promising therapeutic strategy for LUAD.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 13.6
- 新锐分区
- 1区