BET 抑制剂 (BETi) 通过影响线粒体动力学来影响氧化磷酸化代谢，从而导致三阴性乳腺癌 (TNBC) 细胞凋亡途径的改变。
BET inhibitors (BETi) influence oxidative phosphorylation metabolism by affecting mitochondrial dynamics leading to alterations in apoptotic pathways in triple-negative breast cancer (TNBC) cells.
发表日期：2024 Sep 02
作者：
Teresa Rossi, Egidio Iorio, Mattea Chirico, Maria Elena Pisanu, Nicola Amodio, Maria Eugenia Gallo Cantafio, Ida Perrotta, Francesca Colciaghi, Marco Fiorillo, Alessia Gianferrari, Noemi Puccio, Antonino Neri, Alessia Ciarrocchi, Mariaelena Pistoni
来源：
CELL PROLIFERATION
摘要：
使用溴结构域抑制剂 (BETi) 抑制 BET 蛋白的功能已被证明可以通过调节 BRD4 下游基因的转录来引发抗肿瘤作用。我们之前表明，BETi 促进了三阴性乳腺癌 (TNBC) 细胞的细胞死亡。在这里，我们证明 BETi 会导致 TNBC 细胞发生细胞死亡，从而改变线粒体动力学适应性。我们证明，BETi 治疗下调了 BCL-2 和参与线粒体裂变的蛋白质的表达，并增加了融合线粒体。线粒体分裂受损会影响氧化磷酸化 (OXPHOS)，从而诱导 OXPHOS 相关基因 SDHa 和 ATP5a 的表达，并增加细胞死亡。一致地，与对照细胞相比，BETi 处理的细胞中线粒体 DNA 的量和线粒体膜电位 (ΔΨm) 有所增加。最后，BETi 与二甲双胍联合使用可减少细胞生长。我们的结果表明，线粒体动力学和 OXPHOS 代谢支持乳腺癌增殖，并代表 TNBC 细胞中新的 BETi 下游靶标。© 2024 作者。北京干细胞与再生医学研究院和John Wiley联合出版的《细胞增殖》
Repressing BET proteins' function using bromodomain inhibitors (BETi) has been shown to elicit antitumor effects by regulating the transcription of genes downstream of BRD4. We previously showed that BETi promoted cell death of triple-negative breast cancer (TNBC) cells. Here, we proved that BETi induce altered mitochondrial dynamics fitness in TNBC cells falling in cell death. We demonstrated that BETi treatment downregulated the expression of BCL-2, and proteins involved in mitochondrial fission and increased fused mitochondria. Impaired mitochondrial fission affected oxidative phosphorylation (OXPHOS) inducing the expression of OXPHOS-related genes, SDHa and ATP5a, and increased cell death. Consistently, the amount of mitochondrial DNA and mitochondrial membrane potential (∆Ψm) increased in BETi-treated cells compared to control cells. Lastly, BETi in combination with Metformin reduced cell growth. Our results indicate that mitochondrial dynamics and OXPHOS metabolism support breast cancer proliferation and represent novel BETi downstream targets in TNBC cells.© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.