ArticleMolecular and cellular biology2013
Arsenic inhibits autophagic flux, activating the Nrf2-Keap1 pathway in a p62-dependent manner.
Article in Molecular and cellular biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 115 papers.
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115 citing papers in PubMed, 227 citations in OpenAlex.
- The autophagy switch: A critical determinant of arsenic-induced carcinogenesis and cancer therapy.Toxicology reports · 2026Review
- Improved efficiency of protein aggregate removal using ubiquitin with a signal peptide.BMB reports · 2026Article
- Correlative Raman and immunofluorescence imaging reveals different protein abundance between stress granules induced by oxidative damage.Journal of inorganic biochemistry · 2026Article
- Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.PloS one · 2026Article
- Article
- Integrative assessment of RNA sequencing and in silico analysis to pinpoint mRNAs, lncRNAs, and circRNAs interactions with miRNAs underlying arsenic-induced neurotoxicity.BMC genomics · 2025Article
- Targeting Nrf2 in acute myeloid leukemia: an updated review on its role in chemoresistance and emerging therapeutic strategies.Medical oncology (Northwood, London, England) · 2025Review
- Thirty years of NRF2: advances and therapeutic challenges.Nature reviews. Drug discovery · 2025Review
- Heavy metal-induced disruption of the autophagy-lysosomal pathway: implications for aging and neurodegenerative disorders.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2025Review
- Obesity induced by a high-fat diet changes p62 protein levels in mouse reproductive organs.Journal of molecular histology · 2024Article
- Autophagy and cancer therapy.Cancer letters · 2024Review
- Lysosomal genes contribute to Parkinson's disease near agriculture with high intensity pesticide use.NPJ Parkinson's disease · 2024Article
- Advancements in Genetic Biomarkers and Exogenous Antioxidant Supplementation for Safeguarding Mammalian Cells against Heat-Induced Oxidative Stress and Apoptosis.Antioxidants (Basel, Switzerland) · 2024Review
- Endothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunction.Journal of translational medicine · 2024Article
- TFEB and TFE3 cooperate in regulating inorganic arsenic-induced autophagy-lysosome impairment and immuno-dysfunction in primary dendritic cells.Cell biology and toxicology · 2024Article
- Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony.Cellular and molecular life sciences : CMLS · 2023Review
- Apatinib combined with olaparib induces ferroptosis via a p53-dependent manner in ovarian cancer.Journal of cancer research and clinical oncology · 2023Article
- The NRF2-p97-NRF2 negative feedback loop.Redox biology · 2023Article
- Multifaceted role of redox pattern in the tumor immune microenvironment regarding autophagy and apoptosis.Molecular cancer · 2023Review
- Role of Natural and Synthetic Compounds in Modulating NRF2/KEAP1 Signaling Pathway in Prostate Cancer.Cancers · 2023Review
55 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 1 country.
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Abstract
The Nrf2-Keap1 signaling pathway is a protective mechanism promoting cell survival. Activation of the Nrf2 pathway by natural compounds has been proven to be an effective strategy for chemoprevention. Interestingly, a cancer-promoting function of Nrf2 has recently been observed in many types of tumors due to deregulation of the Nrf2-Keap1 axis, which leads to constitutive activation of Nrf2. Here, we report a novel mechanism of Nrf2 activation by arsenic that is distinct from that of chemopreventive compounds. Arsenic deregulates the autophagic pathway through blockage of autophagic flux, resulting in accumulation of autophagosomes and sequestration of p62, Keap1, and LC3. Thus, arsenic activates Nrf2 through a noncanonical mechanism (p62 dependent), leading to a chronic, sustained activation of Nrf2. In contrast, activation of Nrf2 by sulforaphane (SF) and tert-butylhydroquinone (tBHQ) depends upon Keap1-C151 and not p62 (the canonical mechanism). More importantly, SF and tBHQ do not have any effect on autophagy. In fact, SF and tBHQ alleviate arsenic-mediated deregulation of autophagy. Collectively, these findings provide evidence that arsenic causes prolonged activation of Nrf2 through autophagy dysfunction, possibly providing a scenario similar to that of constitutive activation of Nrf2 found in certain human cancers. This may represent a previously unrecognized mechanism underlying arsenic toxicity and carcinogenicity in humans.
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