在乳腺癌大脑转移细胞中,ACSS2以E2F1依赖的方式调节铁
Emily M Esquea1,2, Riley G Young1,2, Lorela Ciraku1,2
1Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102.
bioRxiv : the preprint server for biology
|November 1, 2024
概括
乳腺癌大脑转移依赖乙酸代谢才能生存. 抑制ACSS2引发铁亡,为这些侵袭性瘤提供了一种新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 癌症转移 癌症转移
- 分子生物学分子生物学
背景情况:
- 大脑转移是乳腺癌的破坏性并发症,治疗选择有限.
- 乳腺癌脑转移 (BCBM) 呈现出独特的代谢适应,包括对乙酸盐的依赖.
- 控制BCBM生存的信号通路在很大程度上是未知的.
研究的目的:
- 阐明调节乳腺癌大脑转移中的生存信号通路.
- 研究乙酸代谢,特别是ACSS2在BCBM生长和生存中的作用.
- 探索针对BCBM中ACSS2的新型治疗策略.
主要方法:
- 在BCBM与父细胞中对O-GlcNAc,OGT和ACSS2酸化的比较分析.
- 在实体研究中,在小鼠模型中使用OGT和CDK5的基因操纵.
- 对大脑中的ACSS2功能与乳腺脂肪瘤的评估.
- 通过E2F1和下游目标 (SLC7A11,GPX4) 对ACSS2调节铁的机制研究.
- 在临床前模型中评估一种新型脑透性ACSS2抑制剂.
主要成果:
- 在BCBM细胞中,O-GlcNAc,OGT和ACSS2-Ser267酸化的水平较高.
- 在体内,OGT和CDK5对于BCBM生长至关重要.
- ACSS2活动对大脑转移至关重要,但不是主要瘤的生长.
- ACSS2通过调节SLC7A11和GPX4.4的E2F1-介导表达来抑制BCBM中的铁亡.
- 一种新型的ACSS2抑制剂诱导铁亡并降低BCBM生长ex vivo和in vivo.
结论:
- 通过防止铁亡,ACSS2在BCBM生存中发挥着至关重要的作用.
- 用抑制剂向ACSS2代表了乳腺癌大脑转移的一个有希望的治疗方法.
- BCBM细胞可能对诱导铁亡的药物敏感.
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