Increased intracellular free zinc concentrations are associated with activation of several stress signaling pathways, specific organelle injury and final cell death. In the present work we examined the involvement of mitochondria and lysosomes and their crosstalk in free zinc-induced cell demise. We report that treatment of cervical tumor Hep-2 cells with zinc pyrithione leads to an early appearance of cytoplasmic zinc-specific foci with corresponding accumulation of zinc first in mitochondria and later in lysosomes. Concomitant with these changes, upregulation of expression of metallothionein II A gene as well as the increased abundance of its protein occurs. Moreover, zinc activates p53 and its dependent genes including Puma and Bax and they contribute to an observed loss of mitochondrial membrane potential and activation of apoptosis. Conversely, lysosomal membrane permeabilization and its promoted cleavage of Bid occurs in a delayed manner in treated cells and their effect on decrease of mitochondrial membrane potential is limited. The use of specific inhibitors as well as siRNA technology suggest a crucial role of MT-IIA in trafficking of free zinc into mitochondria or lysosomes and regulation of apoptotic or necrotic cell demise.
- MeSH
- apoptóza účinky léků MeSH
- keratolytika farmakologie MeSH
- lidé MeSH
- lyzozomy metabolismus MeSH
- malá interferující RNA genetika metabolismus MeSH
- matrixové metaloproteinasy metabolismus MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- mitochondrie metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory děložního čípku genetika metabolismus MeSH
- organokovové sloučeniny farmakologie MeSH
- oxidační stres účinky léků MeSH
- proliferace buněk účinky léků MeSH
- pyridiny farmakologie MeSH
- signální transdukce účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zinek metabolismus MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
