Disruption of crosstalk between the fatty acid synthesis and proteasome pathways enhances unfolded protein response signaling and cell death.
Disruption of crosstalk between the fatty acid synthesis and proteasome pathways enhances unfolded protein response signaling and cell death.
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DOI：
10.1158/1535-7163.mct-08-0558
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发表时间：
2008-12
影响因子：
5.7
通讯作者：
Kridel SJ
中科院分区：
文献类型：
--
作者：
Little JL;Wheeler FB;Koumenis C;Kridel SJ
脂肪酸合成酶（Fatty Acid Synthase，FATCH）是负责脂肪酸合成的末端酶，并且在各种来源的肿瘤中上调以促进其生长和进展。由于有几个报告将脂肪酸合成酶和蛋白酶体途径联系起来，我们询问FRENTA抑制剂是否可以与FDA批准的蛋白酶体抑制剂硼替佐米（bortezaline）联合收割机组合，以扩大细胞死亡。事实上，硼替佐米治疗增加了次优的FRESINE抑制剂浓度，以减少克隆形成存活，这被凋亡标志物的增加所抵消。有趣的是，Festival抑制剂诱导泛素化蛋白的积累，并增强硼替佐米治疗的效果。反过来，硼替佐米增加脂肪酸的合成，表明途径之间的串扰。我们假设串扰干扰导致的细胞死亡是由未折叠蛋白反应（UPR）信号传导增加介导的。事实上，干扰激活和饱和UPR信号的适应臂，包括eIF 2 α磷酸化，激活转录因子4（ATF 4）表达和X-box结合蛋白1（XBP-1）剪接。此外，虽然单一药物没有激活UPR的警报阶段，但串扰中断导致激活的JNK和C-EBP同源蛋白（CHOP）依赖性细胞死亡。结合起来，数据支持的概念，即UPR之间的平衡适应压力信号可以被利用来介导增加细胞死亡，并提出了新的应用Festival抑制剂的临床使用。
Fatty Acid Synthase (FASN) is the terminal enzyme responsible for fatty acid synthesis and is upregulated in tumors of various origins to facilitate their growth and progression. Because of several reports linking the fatty acid synthase and proteasome pathways, we asked whether FASN inhibitors could combine with bortezomib, the FDA-approved proteasome inhibitor, to amplify cell death. Indeed, bortezomib treatment augmented sub-optimal FASN inhibitor concentrations to reduce clonogenic survival, which was paralleled by an increase in apoptotic markers. Interestingly, FASN inhibitors induced accumulation of ubiquinated proteins and enhanced the effects of bortezomib treatment. In turn, bortezomib increased fatty acid synthesis, suggesting crosstalk between the pathways. We hypothesized that cell death resulting from crosstalk perturbation was mediated by increased unfolded protein response (UPR) signaling. Indeed, disruption of crosstalk activated and saturated the adaptation arm of UPR signaling, including eIF2α phosphorylation, activating transcription factor 4 (ATF4) expression, and X-box binding protein 1 (XBP-1) splicing. Furthermore, while single agents did not activate the alarm phase of the UPR, crosstalk interruption resulted in activated JNK and C-EBP homologous protein (CHOP)-dependent cell death. Combined, the data support the concept that the UPR balance between adaptive to stress signaling can be exploited to mediate increased cell death and suggests novel applications of FASN inhibitors for clinical use.