Cadmium induces autophagy through ROS-dependent activation of the LKB1-AMPK signaling in skin epidermal cells

Young Ok Son, Xin Wang, John Andrew Hitron, Zhuo Zhang, Senping Cheng, Amit Budhraja, Songze Ding, Jeong Chae Lee, Xianglin Shi

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

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.

Original languageEnglish
Pages (from-to)287-296
Number of pages10
JournalToxicology and Applied Pharmacology
Volume255
Issue number3
DOIs
StatePublished - Sep 15 2011

Bibliographical note

Funding Information:
We thank Dr. Jia Luo (University of Kentucky) for GFP-LC3 plasmid, Dr. J. Suttles (University of Louisville) for CA-AMPKα and DN-AMPKα constructs, and Hong Lin for technical help. This research was supported by NIH grants ( R01ES015518 , 1R01CA119028 , R01ES015375 , and 1R01CA116697 ).

Keywords

  • AMPK
  • Autophagy
  • Cadmium
  • LKB1
  • MTOR
  • ROS

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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