2. Academic Validation
  3. ATF4/PHGDH mediates the effects of ER stress on cadmium-induced autophagy and glycolysis

ATF4/PHGDH mediates the effects of ER stress on cadmium-induced autophagy and glycolysis

  • Toxicology. 2024 Dec:509:153976. doi: 10.1016/j.tox.2024.153976.
Yanqiu Yang 1,  Shengnan Li 2,  Yuanxi Yang 3,  Qiujuan Li 2,  Yong Liu 4,  Jun Cao 5
Affiliations

Affiliations

  • 1 Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China; Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China.
  • 2 Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
  • 3 Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China; Department of Clinical Nutrition, Ansteel Group General Hospital, Anshan 114000, China.
  • 4 School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China. Electronic address: yliu@dlut.edu.cn.
  • 5 Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China. Electronic address: caojunly@163.com.
PMID: 39427783 DOI: 10.1016/j.tox.2024.153976
Abstract

Cadmium (Cd) has been classified as a Class I carcinogen, but the mechanism of its carcinogenicity is still unknown. Our previous study demonstrated that 2 μM CdCl2 induced Autophagy in A549 cells. In this study, we investigated the role of ATF4/PHGDH in Cd-induced Autophagy and increased glycolysis. First, BALB/c mice were subcutaneously injected with A549 cells co-treated with or without Cd and siPHGDH to establish a xenograft tumor model, which demonstrated that PHGDH promotes Cd-induced Autophagy in vivo. Cd-exposed A549 cells were treated with siPHGDH and 0.4 mM glycine (Gly), respectively. Western blot analysis and Acridine orange staining revealed that PHGDH promotes Cd-induced Autophagy. Using 4-PBA (5 mM), the inhibitor of ER stress, or Tm (0.1 μg/ml), the inducer of ER stress, inhibited Cd-induced PHGDH expression. After co-treatment with siPHGDH, PHGDH was determined to mediate ER stress-induced Autophagy. Furthermore, transfection with siATF4 inhibited Tm-induced PHGDH expression. ChIP-qPCR experiments demonstrated the transcription regulatory mechanism of ATF4 on PHGDH. Meanwhile, the role of ER stress/PHGDH/Autophagy in Cd-promoted cell migration was explored by scratch assay. Finally, the role of ER stress/PHGDH/Autophagy in Cd-induced glycolysis was unveiled. In summary, the transcriptional regulation of PHGDH by ATF4 plays a crucial role in Cd-induced Autophagy triggered by ER stress. The axis of ER stress/PHGDH/Autophagy is important in Cd-induced cell migration by enhancing glycolysis.

Keywords

ATF4; Autophagy; Cadmium; ER stress; PHGDH.

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