2. Academic Validation
  3. Cadmium inhibits apoptosis of human esophageal epithelial cells by upregulating CDK6

Cadmium inhibits apoptosis of human esophageal epithelial cells by upregulating CDK6

  • Ecotoxicol Environ Saf. 2020 Dec 1;205:111146. doi: 10.1016/j.ecoenv.2020.111146.
Jian Yang 1,  Tianyi Guo 2,  Xiao Liang 3,  Yuanfang Zhai 4,  Yikun Cheng 5,  Hui Sun 6,  Yongping Cui 7,  Xiaolong Cheng 8
Affiliations

Affiliations

  • 1 Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, PR China; Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan, PR China.
  • 2 Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan, PR China; Department of Colorectal Anorectum, Shanxi Provincial People's Hospital Affilicated of Shanxi Medical University, Taiyuan, PR China.
  • 3 Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan, PR China; Department of Anatomy, Shanxi Medical University, Taiyuan, PR China; Department of Orthopedics, Second Hospital of Shanxi Medical University, Taiyuan, PR China.
  • 4 Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan, PR China; Department of Anatomy, Shanxi Medical University, Taiyuan, PR China.
  • 5 College of Letter & Science, University of California Berkeley, Berkeley, USA.
  • 6 Institute of Science & Technology of Shanxi, Taiyuan, PR China.
  • 7 Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, PR China; Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan, PR China. Electronic address: cuiyp@sxmu.edu.cn.
  • 8 Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan, PR China; Department of Anatomy, Shanxi Medical University, Taiyuan, PR China. Electronic address: chengxl@sxmu.edu.cn.
PMID: 32827965 DOI: 10.1016/j.ecoenv.2020.111146
Abstract

Cadmium (Cd) exposure in environment is associated with development of esophageal Cancer. However, the mechanisms of Cd-induced carcinogenesis are still not been fully cleared, and the present study aimed to explore the possible etiological mechanism of Cd-induced esophageal Cancer. Human esophageal epithelial cell lines (HET-1A and KYSE450) were treated with CdCl2 at 0.05 mg/l for 12, 24 h, and the then the Apoptosis were detected using flow cytometry with annexin-V-FITC/PI staining. Results showed that Apoptosis of treatment groups was significantly inhibited, and decreased Reactive Oxygen Species (ROS) production played a key role in the inhibitory effects by upregulating Bcl-2 and downregulating Caspase-3/9. The relief of oxidative stress during Cd exposure was actively promoted by the increased nicotinamide adenine dinucleotide phosphoric acid and glutathione levels. To investigate the causes of enhanced intracellular antioxidant capacity, the activity of Pyruvate Kinase (PK), a key Enzyme of glycolysis, was detected. Our results showed that PK activity was inhibited, suggesting that glycolysis process was blocked which promoted more intermediate metabolites of glycolysis to be used for reduced nicotinamide adenine dinucleotide phosphoric acid (NADPH) or other Antioxidants synthesis. PK activity was closely correlated with phosphorylation of Pyruvate Kinase M2 (PKM2), and a highly negative correlation (correlation coefficients: -0.835, p < 0.05) between them was found. Western blotting showed the overphosphorylation of PKM2 in Cd-exposed cells, resulting from increased expression of cyclin-dependent kinases 6 (CDK6). These results suggested a possible mechanism of carcinogenic: Cd-induced upregulation of CDK6 in esophageal cell lines caused PKM2 overphosphorylation inhibiting PK activity, thereby shunting glucose-derived carbon into the pentose phosphate pathway and promoting the production of NADPH and reduced glutathione (GSH) to neutralize ROS, which finally results in the inhibited Apoptosis.

Keywords

Cadmium; Cyclin-dependent kinases 6; Esophageal cancer; Pyruvate kinase M2 phosphorylation; Pyruvate kinase activity.

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