Maaser Kerstin, Sutter Andreas P, Scherübl Hans
Medical Clinic I, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12200 Berlin, Germany.
Biochem Biophys Res Commun. 2005 Jul 8;332(3):646-52. doi: 10.1016/j.bbrc.2005.05.005.
Specific ligands of the peripheral benzodiazepine receptor (PBR) have been shown to induce apoptosis in gastrointestinal cancers. The aim of this study was to characterize the signaling pathways of PBR ligand-induced apoptosis. FGIN-1-27 but not PK 11195-induced apoptosis was associated with a decrease of mitochondrial membrane potential and an increase of mitochondrial volume in HT29 colorectal cancer cells. However, PK 11195-elicited apoptosis was associated with a downregulation of Bcl-2, translocation of Bax to the mitochondria including subsequent oligomerization, and activation of caspase-9, indicating the involvement of mitochondria in PK 11195-induced apoptosis. Moreover, PK 11195-induced apoptosis was associated with the generation of reactive oxygen species. This study demonstrates a novel mechanism of PK 11195-induced mitochondrial apoptosis without alteration of the mitochondrial membrane potential. The characterization of signaling pathways associated with PBR ligand-induced apoptosis will build the base for a future use of these ligands in anti-neoplastic therapeutic approaches.
外周苯二氮䓬受体（PBR）的特异性配体已被证明可诱导胃肠道癌细胞凋亡。本研究的目的是表征PBR配体诱导凋亡的信号通路。在HT29结肠癌细胞中，FGIN-1-27而非PK 11195诱导的凋亡与线粒体膜电位降低和线粒体体积增加有关。然而，PK 11195引发的凋亡与Bcl-2下调、Bax转位至线粒体（包括随后的寡聚化）以及caspase-9激活有关，表明线粒体参与了PK 11195诱导的凋亡。此外，PK 11195诱导的凋亡与活性氧的产生有关。本研究证明了PK 11195诱导线粒体凋亡的新机制，且线粒体膜电位未发生改变。与PBR配体诱导凋亡相关的信号通路表征将为这些配体未来在抗肿瘤治疗方法中的应用奠定基础。
