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Arsenic inhibits autophagic flux, activating the Nrf2-Keap1 pathway in a p62-dependent manner

Alexandria Lau1, Yi Zheng, Shasha Tao

  • 1Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, USA.

Molecular and Cellular Biology
|April 17, 2013
PubMed

Insights

Arsenic activates the Nrf2-Keap1 pathway via autophagy disruption, unlike cancer-preventive compounds. This novel mechanism causes sustained Nrf2 activation, potentially contributing to arsenic

Area of Science:

  • Cellular signaling pathways
  • Toxicology and carcinogenicity
  • Autophagy and cancer research

Background:

  • The Nrf2-Keap1 pathway is crucial for cell survival and chemoprevention.
  • Dysregulated Nrf2-Keap1 signaling contributes to cancer development.
  • Arsenic's role in cellular toxicity and carcinogenicity requires further elucidation.

Purpose of the Study:

  • To investigate a novel mechanism of Nrf2 activation by arsenic.
  • To differentiate arsenic-induced Nrf2 activation from that of chemopreventive agents.
  • To explore the role of autophagy in arsenic-mediated Nrf2 activation.

Main Methods:

  • Investigated arsenic's effect on the Nrf2-Keap1 pathway and autophagy.
  • Compared arsenic's mechanism with canonical activators like sulforaphane (SF) and tert-butylhydroquinone (tBHQ).
  • Analyzed autophagosome accumulation and sequestration of key proteins (p62, Keap1, LC3).

Main Results:

  • Arsenic activates Nrf2 via a noncanonical, p62-dependent mechanism by disrupting autophagic flux.
  • Chemopreventive compounds SF and tBHQ activate Nrf2 via a canonical Keap1-dependent mechanism and do not affect autophagy.
  • SF and tBHQ can alleviate arsenic-induced autophagy deregulation.

Conclusions:

  • Arsenic induces prolonged Nrf2 activation through autophagy dysfunction.
  • This mechanism may mimic the constitutive Nrf2 activation observed in cancers.
  • Findings suggest a novel pathway for arsenic toxicity and carcinogenicity.

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