Zeb1-mediated control of the PUFA/MUFA ratio in EMT-associated ferroptosis sensitivity

Zeb1介导的对EMT相关铁死亡敏感性中PUFA/MUFA比率的控制

• 批准号: 461704629
• 负责人: Professor Dr. Thomas Brabletz
• 金额: --
• 依托单位: Nikolaus-Fiebiger-Zentrum für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/461704629?language=en
• 关键词: Zeb1; mediated; control; PUFA; MUFA

Ferroptosis is a highly conserved cell death pathway, depending on an iron and oxygen-radical mediated peroxidation of phospholipids. Importantly, such phospholipids need to be composed of certain species of polyunsaturated fatty acids (PUFAs). In contrast to apoptosis, the prominent death pathway in differentiated cells (e.g. epithelial cells), ferroptosis can be executed predominantly in undifferentiated cells and cells with a (partial) mesenchymal phenotype. In cancer cells this phenotype is often acquired by activation of the epithelial-mesenchymal transition (EMT) program, and associated with high metastatic competence and therapy-resistance. We could demonstrate that the EMT-activating transcription factor Zeb1 strongly increases PUFA-levels, whereas it decreases the counteracting monounsaturated fatty acids (MUFAs). We will proof if Zeb1 directly regulates the expression of the rate-limiting enzymes for PUFA- vs. MUFA-synthesis, i.e. downregulates expression of stearyl Co-A desaturase 1 (SCD1), which is critical for MUFA synthesis, and upregulates expression of fatty acid desaturase 2 (FADS2) and elongation of very long chain fatty acid 5 (ELOVL5), both rate-limiting enzymes for PUFA synthesis. We will further proof if altered expression and function of these enzymes accounts for the Zeb1-associated ferroptosis sensitivity in cancer cells with a (partial) mesenchymal phenotype. Finally, we will test if specific modulators of their expression and function will support ferroptosis activation as therapeutic strategy against highly aggressive cancer types.

铁铁作用是一种高度保守的细胞死亡途径，具体取决于磷脂的铁和氧基中介导的过氧化。重要的是，这种磷脂需要由某些多不饱和脂肪酸（PUFAS）组成。与细胞凋亡相反，分化细胞（例如上皮细胞）的突出死亡途径可以在未分化的细胞和具有（部分）间充质表型的细胞和细胞中执行螺旋病。在癌细胞中，这种表型通常是通过上皮 - 间质转变（EMT）程序而获得的，并且与高转移能力和耐药性相关。我们可以证明，EMT激活转录因子Zeb1强烈增加了PUFA级别，而它减少了反破坏单不饱和脂肪酸（MUFA）。我们将证明Zeb1是否直接调节用于pufa-vs. Mufa合成的速率限制酶的表达，即下调stearyl Co-A Co-A去饱和酶1（SCD1）的表达，这对于MUFA合成至关重要，并且上调了脂肪的表达酸去饱和酶2（FADS2）和非常长的链脂肪酸5（Elovl5）的伸长，这都是PUFA合成的限制酶。我们将进一步证明这些酶的表达和功能是否解释了具有（部分）间充质表型的癌细胞中与Zeb1相关的铁毒性敏感性。最后，我们将测试其表达和功能的特定调节剂是否将支持逆吞作用作为针对高度侵略性癌症类型的治疗策略。