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Cadmium induces autophagy through ROS-dependent activation of the LKB1-AMPK signaling in skin epidermal cells
- Publication Year :
- 2011
-
Abstract
- Cadmium is a toxic heavy metal which is environmentally and occupationally relevant. The mechanisms underlying cadmium-induced autophagy are not yet completely understood. The present study shows that cadmium induces autophagy, as demonstrated by the increase of LC3-II formation and the GFP-LC3 puncta cells. The induction of autophagosomes was directly visualized by electron microscopy in cadmium-exposed skin epidermal cells. Blockage of LKB1 or AMPK by siRNA transfection suppressed cadmium-induced autophagy. Cadmium-induced autophagy was inhibited in dominant-negative AMPK-transfected cells, whereas it was accelerated in cells transfected with the constitutively active form of AMPK. mTOR signaling, a negative regulator of autophagy, was downregulated in cadmium-exposed cells. In addition, cadmium generated reactive oxygen species (ROS) at relatively low levels, and caused poly(ADP-ribose) polymerase-1 (PARP) activation and ATP depletion. Inhibition of PARP by pharmacological inhibitors or its siRNA transfection suppressed ATP reduction and autophagy in cadmium-exposed cells. Furthermore, cadmium-induced autophagy signaling was attenuated by either exogenous addition of catalase and superoxide dismutase, or by overexpression of these enzymes. Consequently, these results suggest that cadmium-mediated ROS generation causes PARP activation and energy depletion, and eventually induces autophagy through the activation of LKB1-AMPK signaling and the down-regulation of mTOR in skin epidermal cells.
- Subjects :
- inorganic chemicals
Small interfering RNA
AMP-Activated Protein Kinases
Protein Serine-Threonine Kinases
Toxicology
Article
Cell Line
Superoxide dismutase
Mice
Autophagy
Animals
PI3K/AKT/mTOR pathway
Pharmacology
chemistry.chemical_classification
Reactive oxygen species
biology
AMPK
Transfection
Cell biology
chemistry
Cell culture
biology.protein
Epidermis
Reactive Oxygen Species
Cadmium
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....336387e1dc6e3a2e48543e1a59bcbbb9