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

Environmental Health Perspectives
Lishi XieGail S Prins

Abstract

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. We studied how iAs affects normal human prostate stem-progenitor cells (PrSPCs) and drives transformation and interrogated the molecular mechanisms involved. 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 μ M ) iAs in drinking water for 3 months. Low-dose iAs ( 1 μ M ) disturbed PrSPC homeostasis in vitro, leading to increased self-renewal and suppressed differentiation. Transcriptomic analysis indicated that iAs activated o...Continue Reading

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Citations

Jan 23, 2021·Differentiation; Research in Biological Diversity·Gail S Prins
Aug 28, 2021·Cancers·Fiorenza GianìRiccardo Vigneri

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Methods Mentioned

BETA
FACS
PCR
Assay
dissecting
nuclear translocation
DNA seq
lipidation
Flow cytometry
gene knockdown

Software Mentioned

Wikipathway
GEne SeT AnaLysis Toolkit
GSEA
Limma R package
GraphPad
ImageJ
Wikipathway Analysis
GraphPad Prism

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