2. Academic Validation
  3. Arsenic activated GLUT1-mTORC1/HIF-1α-PKM2 positive feedback networks promote proliferation and migration of bladder epithelial cells

Arsenic activated GLUT1-mTORC1/HIF-1α-PKM2 positive feedback networks promote proliferation and migration of bladder epithelial cells

  • Sci Total Environ. 2024 Jul 6:947:174538. doi: 10.1016/j.scitotenv.2024.174538.
Zhushan Fu 1,  Meiqi Deng 2,  Qing Zhou 1,  Sihao Li 1,  Weijue Liu 1,  Siyan Cao 1,  Lei Zhang 1,  Yu Deng 3,  Shuhua Xi 4
Affiliations

Affiliations

  • 1 Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, Liaoning 110122, China; The Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, Shenyang, Liaoning 110122, China; Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China.
  • 2 Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, Liaoning 110122, China; Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
  • 3 Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, Liaoning 110122, China; The Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, Shenyang, Liaoning 110122, China; Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: ydeng@cmu.edu.cn.
  • 4 Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, Liaoning 110122, China; The Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, Shenyang, Liaoning 110122, China; Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: shxi@cmu.edu.cn.
PMID: 38977090 DOI: 10.1016/j.scitotenv.2024.174538
Abstract

Arsenic (As) is recognized as a potent environmental contaminant associated with bladder carcinogenesis. However, its molecular mechanism remains unclear. Metabolic reprogramming is one of the hallmarks of Cancer and is as a central feature of malignancy. Here, we performed the study of cross-talk between the mammalian target of rapamycin complex 1 (mTORC1)/ Hypoxia-inducible factor 1 alpha (HIF-1α) pathway and aerobic glycolysis in promoting the proliferation and migration of bladder epithelial cells treated by arsenic in vivo and in vitro. We demonstrated that arsenite promoted N-methyl-N-nitrosourea (MNU)-induced tumor formation in the bladder of rats and the malignant behavior of human ureteral epithelial (SV-HUC-1) cell. We found that arsenite positively regulated the mTORC1/HIF-1α pathway through glucose transporter protein 1 (GLUT1), which involved in the malignant progression of bladder epithelial cells relying on glycolysis. In addition, Pyruvate Kinase M2 (PKM2) increased by arsenite reduced the protein expressions of Succinate Dehydrogenase (SDH) and fumarate hydratase (FH), leading to the accumulation of tumor metabolites of succinate and fumarate. Moreover, heat shock protein (HSP)90, functioning as a chaperone protein, stabilized PKM2 and thereby regulated the proliferation and aerobic glycolysis in arsenite treated SV-HUC-1 cells. Taken together, these results provide new insights into mTORC1/HIF-1α and PKM2 networks as critical molecular targets that contribute to the arsenic-induced malignant progression of bladder epithelial cells.

Keywords

Arsenite; Bladder epithelial cell; Malignant progression; PKM2; mTORC1/HIF-1α signaling.

Figures
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  • HY-19331
    99.93%, Glut1抑制剂
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