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Arsenic-induced disruption of circadian rhythms and glutamine anaplerosis in human urothelial carcinoma.
Chang, Shu-Jyuan; Chen, Wan-Tzu; Chai, Chee-Yin.
Afiliación
  • Chang SJ; Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
  • Chen WT; Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
  • Chai CY; Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University Kaohsiung, Taiwan. Electronic address: cychai@kmu.edu.tw.
J Trace Elem Med Biol ; 86: 127507, 2024 Aug 02.
Article en En | MEDLINE | ID: mdl-39137608
ABSTRACT
Inorganic arsenic (iAs)-induced urothelial carcinoma (UC) develops into a poor-prognosis malignancy. Arsenic-induced oxidative stress contributes to circadian rhythm disruption altered metabolism. Glutamine anaplerosis is a common metabolic feature of rapidly proliferating malignant cells, in which glutaminase (GLS) is a key enzyme in this process. Therefore, this study intends to determine if arsenic-induced oxidative stress can alter circadian rhythms and promote glutamine anaplerosis. Exonic expression of core circadian molecules (CLOCK, ARNTL, and NR1D1) and GLS in varying grades of UC were assessed using 423 bladder cancer samples from the TCGA Urothelial Bladder Cancer (BLCA) dataset. The levels of circadian proteins and metabolic markers in 44 UC patients from non-black foot disease (BFD) and BFD areas were detected by immunohistochemistry. In vitro and in vivo experiments elucidated the regulatory mechanisms of arsenic-mediated circadian disturbance and metabolic alteration. Public database analysis showed that ARNTL, NR1D1, and GLS exhibited greater expression in more high-grade UC. Strong immunoreactivity for BMAL1, GLS, and low levels of NR1D1 were found in malignant urothelial lesions, especially in arsenic-exposed UC. Arsenic-induced overexpression of BMAL1 and GLS involves activation of NADH quinone oxidoreductase 1 (NQO1), continuously altering the NADH oscillations to promote glutamate metabolism in SV-HUC-1, T24 and BFTC-905 cells. These phenomenon were also demonstrated in the urothelium of arsenic-exposed animals. The present findings highlight the potential clinical significance of BMAL1 and GLS in UC in the BFD region. Furthermore, these results suggest that arsenic interferes with circadian rhythm and glutamine anaplerosis by NADH oscillatory imbalance in urothelial cells and urothelial cancer cells, predisposing them to malignant development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Trace Elem Med Biol Asunto de la revista: METABOLISMO / SAUDE AMBIENTAL Año: 2024 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Alemania

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Trace Elem Med Biol Asunto de la revista: METABOLISMO / SAUDE AMBIENTAL Año: 2024 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Alemania