title: Cadmium induces autophagy through ROS-dependent activation of the LKB1-AMPK signaling in skin epidermal cells.
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.
authors.affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536-0305, USA.
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Son
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: John Andrew
authors.initials: JA
authors.lastname: Hitron
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Senping
authors.initials: S
authors.lastname: Cheng
authors.forename: Amit
authors.initials: A
authors.lastname: Budhraja
authors.forename: Songze
authors.initials: S
authors.lastname: Ding
authors.forename: Jeong-Chae
authors.initials: JC
authors.lastname: Lee
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002104:Cadmium / Q000633:toxicity*; D002460:Cell Line; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species; D002104:Cadmium; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases