Effects of Inorganic Arsenic on Human Prostate Stem-Progenitor Cell Transformation, Autophagic Flux Blockade, and NRF2 Pathway Activation.

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  • Additional Information
    • Affiliation:
      Department of Urology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
      Chicago Center for Health and Environment, Chicago, Illinois, USA
      Division of Cardiothoracic Surgery, The Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA
      Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
      Departments of Physiology & Biophysics and Pathology, College of Medicine; Division of Epidemiology & Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, Illinois, USA
      University of Illinois Cancer Center, Chicago, Illinois, USA
    • Subject Terms:
    • Subject Terms:
    • Abstract:
      BACKGROUND: Inorganic arsenic (iAs) is an environmental toxicant associated with an increased risk of prostate cancer in chronically exposed populations worldwide. However, the biological mechanisms underlying iAs-induced prostate carcinogenesis remain unclear. OBJECTIVES: We studied how iAs affects normal human prostate stem-progenitor cells (PrSPCs) and drives transformation and interrogated the molecular mechanisms involved. METHODS: PrSPCs were enriched by spheroid culture from normal human primary or immortalized prostate epithelial cells, and their differentiation capability was evaluated by organoid culture. Microarray analysis was conducted to identify iAs-dysregulated genes, and lentiviral infection was used for stable manipulation of identified genes. Soft agar colony growth assays were applied to examine iAs-induced transformation. For in vivo study, PrSPCs mixed with rat urogenital sinus mesenchyme were grafted under the renal capsule of nude mice to generate prostatelike tissues, and mice were exposed to 5 ppm (~65 μM) iAs in drinking water for 3 months. RESULTS: Low-dose iAs (1 lM) disturbed PrSPC homeostasis in vitro, leading to increased self-renewal and suppressed differentiation. Transcriptomic analysis indicated that iAs activated oncogenic pathways in PrSPCs, including the KEAP1-NRF2 pathway. Further, iAs-exposed proliferative progenitor cells exhibited NRF2 pathway activation that was sustained in their progeny cells. Knockdown of NRF2 inhibited spheroid formation by driving PrSPC differentiation, whereas its activation enhanced spheroid growth. Importantly, iAs-induced transformation was suppressed by NRF2 knockdown. Mechanistically, iAs suppressed Vacuolar ATPase subunit VMA5 expression, impairing lysosome acidification and inhibiting autophagic protein degradation including p62, which further activated NRF2. In vivo, chronic iAs exposure activated NRF2 in both epithelial and stroma cells of chimeric human prostate grafts and induced premalignant events. CONCLUSIONS: Low-dose iAs increased self-renewal and decreased differentiation of human PrSPCs by activating the p62-NRF2 axis, resulting in epithelial cell transformation. NRF2 is activated by iAs through specific autophagic flux blockade in progenitor cells, which may have potential therapeutic implications.
    • Journal Subset:
      Blind Peer Reviewed; Editorial Board Reviewed; Peer Reviewed; Public Health; USA
    • ISSN:
      0091-6765
    • MEDLINE Info:
      NLM UID: 0330411
    • Grant Information:
      This study was supported by National Institutes of Health grants R01-ES02207 and P30-ES027792, and by The Michael Reese Research and Education Foundation.
    • Publication Date:
      20200716
    • Publication Date:
      20200724
    • DOI:
      10.1289/EHP6471
    • Accession Number:
      144545517
  • Citations
    • ABNT:
      LISHI XIE et al. Effects of Inorganic Arsenic on Human Prostate Stem-Progenitor Cell Transformation, Autophagic Flux Blockade, and NRF2 Pathway Activation. Environmental Health Perspectives, [s. l.], v. 128, n. 6, p. 067008-1-067008-16, 2020. DOI 10.1289/EHP6471. Disponível em: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=rzh&AN=144545517. Acesso em: 30 set. 2020.
    • AMA:
      Lishi Xie, Wen-Yang Hu, Dan-Ping Hu, et al. Effects of Inorganic Arsenic on Human Prostate Stem-Progenitor Cell Transformation, Autophagic Flux Blockade, and NRF2 Pathway Activation. Environmental Health Perspectives. 2020;128(6):067008-1-067008-16. doi:10.1289/EHP6471
    • APA:
      Lishi Xie, Wen-Yang Hu, Dan-Ping Hu, Guangbin Shi, Ye Li, Jianfu Yang, & Prins, G. S. (2020). Effects of Inorganic Arsenic on Human Prostate Stem-Progenitor Cell Transformation, Autophagic Flux Blockade, and NRF2 Pathway Activation. Environmental Health Perspectives, 128(6), 067008-1-067008-16. https://doi.org/10.1289/EHP6471
    • Chicago/Turabian: Author-Date:
      Lishi Xie, Wen-Yang Hu, Dan-Ping Hu, Guangbin Shi, Ye Li, Jianfu Yang, and Gail S. Prins. 2020. “Effects of Inorganic Arsenic on Human Prostate Stem-Progenitor Cell Transformation, Autophagic Flux Blockade, and NRF2 Pathway Activation.” Environmental Health Perspectives 128 (6): 067008-1-067008-16. doi:10.1289/EHP6471.
    • Harvard:
      Lishi Xie et al. (2020) ‘Effects of Inorganic Arsenic on Human Prostate Stem-Progenitor Cell Transformation, Autophagic Flux Blockade, and NRF2 Pathway Activation’, Environmental Health Perspectives, 128(6), pp. 067008-1-067008-16. doi: 10.1289/EHP6471.
    • Harvard: Australian:
      Lishi Xie, Wen-Yang Hu, Dan-Ping Hu, Guangbin Shi, Ye Li, Jianfu Yang & Prins, GS 2020, ‘Effects of Inorganic Arsenic on Human Prostate Stem-Progenitor Cell Transformation, Autophagic Flux Blockade, and NRF2 Pathway Activation’, Environmental Health Perspectives, vol. 128, no. 6, pp. 067008-1-067008-16, viewed 30 September 2020, .
    • MLA:
      Lishi Xie, et al. “Effects of Inorganic Arsenic on Human Prostate Stem-Progenitor Cell Transformation, Autophagic Flux Blockade, and NRF2 Pathway Activation.” Environmental Health Perspectives, vol. 128, no. 6, June 2020, pp. 067008-1-067008-16. EBSCOhost, doi:10.1289/EHP6471.
    • Chicago/Turabian: Humanities:
      Lishi Xie, Wen-Yang Hu, Dan-Ping Hu, Guangbin Shi, Ye Li, Jianfu Yang, and Gail S. Prins. “Effects of Inorganic Arsenic on Human Prostate Stem-Progenitor Cell Transformation, Autophagic Flux Blockade, and NRF2 Pathway Activation.” Environmental Health Perspectives 128, no. 6 (June 2020): 067008-1-067008-16. doi:10.1289/EHP6471.
    • Vancouver/ICMJE:
      Lishi Xie, Wen-Yang Hu, Dan-Ping Hu, Guangbin Shi, Ye Li, Jianfu Yang, et al. Effects of Inorganic Arsenic on Human Prostate Stem-Progenitor Cell Transformation, Autophagic Flux Blockade, and NRF2 Pathway Activation. Environmental Health Perspectives [Internet]. 2020 Jun [cited 2020 Sep 30];128(6):067008-1-067008-16. Available from: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=rzh&AN=144545517