4-HPR-mediated leukemia cell cytotoxicity is triggered by ceramide-induced mitochondrial oxidative stress and is regulated downstream by Bcl-2 |
| |
Authors: | Morales Maria-Celia Pérez-Yarza Gorka Rementería Naiara N Boyano María-Dolores Apraiz Aintzane Gómez-Muñoz Antonio Pérez-Andrés Encarna Asumendi Aintzane |
| |
Affiliation: | a Department of Cell Biology and Histology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Bizkaia, Spainb Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country, Leioa, Bizkaia, Spain |
| |
Abstract: | We have previously reported that, in leukemia cells, the cytotoxicity of the anticancer agent N-(4-hydroxyphenyl)retinamide (4-HPR) is mediated by mitochondria-derived reactive oxygen species (ROS) and cardiolipin peroxidation. Here, we have analyzed at greater depth the 4-HPR-triggered molecular events, demonstrating that 4-HPR induces an early (15 min) increase in ceramide levels by sphingomyelin hydrolysis and later (from 1 h) by de novo synthesis. Using specific inhibitors of both pathways, we demonstrate that ceramide accumulation is responsible for early ROS generation, which act as apoptotic signalling intermediates leading to conformational activation of Bak and Bax, loss of mitochondrial membrane potential (ΔΨm), mitochondrial membrane permeabilization (MMP) and cell death. Enforced expression of Bcl-2 has no effect on 4-HPR-induced oxidative stress, but notably prevents mitochondrial alterations and apoptosis, indicating that Bcl-2 functions by regulating events downstream of ROS generation. In conclusion, our study delineates for the fist time the sequence and timing of the principal events induced by 4-HPR in leukemia cells and points to the potential use of modulators of ceramide metabolism as enhancers in 4-HPR-based therapies. |
| |
Keywords: | 4-HPR fenretinide ROS apoptosis ceramide Bcl-2 |
本文献已被 InformaWorld PubMed 等数据库收录! |
|