Departament de Ciències Fisiològiques, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona-IDIBELL (Institut d'Investigació Biomèdica de Bellvitge), L'Hospitalet de Llobregat, Barcelona, Spain.
Laboratory of Medical Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Medicine (IBUB), University of Barcelona, Barcelona, Spain.
Apoptosis. 2021 Feb;26(1-2):83-95. doi: 10.1007/s10495-020-01651-z. Epub 2021 Jan 2.
We previously showed that fluorizoline, a fluorinated thiazoline compound, binds to both subunits of the mitochondrial prohibitin (PHB) complex, PHB1 and PHB2, being the expression of these proteins required for fluorizoline-induced apoptosis in mouse embryonic fibroblasts. To investigate the conservation of this apoptotic mechanism, we studied the effect of PHB downregulation on fluorizoline activity on two human cell lines, HEK293T and U2OS. Then, we asked whether PHBs mediate the effect of fluorizoline in a multicellular organism. Interestingly, reduced levels of PHBs in the human cells impaired the induction of apoptosis by fluorizoline. We observed that fluorizoline has a detrimental dose-dependent effect on the development and survival of the nematode model Caenorhabditis elegans. Besides, such effects of fluorizoline treatment in living nematodes were absent in PHB mutants. Finally, we further explored the apoptotic pathway triggered by fluorizoline in human cell lines. We found that the BH3-only proteins NOXA, BIM and PUMA participate in fluorizoline-induced apoptosis and that the induction of NOXA and PUMA is dependent on PHB expression.
我们之前曾表明，氟利嗪啉（一种氟化噻唑啉化合物）与线粒体抑素（PHB）复合物的两个亚基 PHB1 和 PHB2 结合，这些蛋白质的表达是氟利嗪啉诱导小鼠胚胎成纤维细胞凋亡所必需的。为了研究这种凋亡机制的保守性，我们研究了 PHB 下调对两种人细胞系 HEK293T 和 U2OS 中氟利嗪啉活性的影响。然后，我们询问 PHB 是否在多细胞生物中介导氟利嗪啉的作用。有趣的是，人细胞中 PHB 水平的降低削弱了氟利嗪啉诱导凋亡的能力。我们观察到氟利嗪啉对秀丽隐杆线虫模型的发育和生存具有有害的剂量依赖性影响。此外，在 PHB 突变体中不存在氟利嗪啉处理对线虫的这种影响。最后，我们进一步探索了氟利嗪啉在人细胞系中引发的凋亡途径。我们发现 BH3 仅蛋白 NOXA、BIM 和 PUMA 参与氟利嗪啉诱导的凋亡，并且 NOXA 和 PUMA 的诱导依赖于 PHB 的表达。
