title: From the Cover: Autophagy Induction Contributes to Cadmium Toxicity in Mesenchymal Stem Cells via AMPK/FOXO3a/BECN1 Signaling.
abstract: Mesenchymal stem cells (MSCs) are a valuable in vitro model for investigating the bone toxicity of cadmium (Cd). Autophagy has been proposed to play a pivotal role in Cd-mediated toxicity. The FOXO family proteins are important transcription factors that are essential to autophagy induction. This study investigated the role of autophagy in Cd-induced skeleton damage and its potential mechanism. We exposed MSCs to different concentrations of cadmium chloride (3.5, 7, and 14 μM) for 24 h. We demonstrated that Cd treatment increased autophagic flux, and inhibition of autophagic process using BENC1 gene silencing blocked Cd-induced cell death. Cd treatment also significantly increased mRNA levels of various essential autophagy-related genes including ATG5, ATG12, BECN1, LC3, and ULK1. Specifically, Cd increased FOXO3a and FOXO1 expression at the mRNA and protein levels, and AMPK was demonstrated to enhance FOXO3a nuclear translocation and transcriptional activity by phosphorylating FOXO3a at specific serine residues (Ser588) in Cd-treated MSCs. Notably, knockdown of FOXO3a, but not FOXO1, prevented autophagy-related genes expression and autophagosome formation after Cd treatment. Taken together, our results demonstrate that Cd-induced cell death via the overactivation of FOXO3a-dependent autophagy. Modulation of the FOXO3a autophagy pathway may offer novel therapeutic approaches for the treatment of Cd-induced bone damage.
authors: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors: Min
authors: M
authors: Yang
authors: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors: Huifeng
authors: H
authors: Pi
authors: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors: Min
authors: M
authors: Li
authors: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors: Shangcheng
authors: S
authors: Xu
authors: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors: Lei
authors: L
authors: Zhang
authors: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors: Jia
authors: J
authors: Xie
authors: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors: Li
authors: L
authors: Tian
authors: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors: Manyu
authors: M
authors: Tu
authors: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors: Mindi
authors: M
authors: He
authors: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors: Yonghui
authors: Y
authors: Lu
authors: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors: Zhengping
authors: Z
authors: Yu
authors: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China lunazhou00@163.com.
authors: Zhou
authors: Z
authors: Zhou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D000071186:Beclin-1 / Q000378:metabolism; D002104:Cadmium / Q000633:toxicity*; D002460:Cell Line; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D051379:Mice; D015398:Signal Transduction
chemical_list: D000071186:Beclin-1; C115010:Becn1 protein, mouse; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D002104:Cadmium; D055372:AMP-Activated Protein Kinases
keywords: AMPK; BECN1; FOXO3a; autophagy; cadmium; mesenchymal stem cells