The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.
Arsenic Inhibits Autophagic Flux, Activating the Nrf2-Keap1 Pathway in a p62-Dependent Manner
Open accessAbstract
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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Cites
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“p62 interacts directly with microtubule-associated protein 1 light chain 3 (LC3), a component of the autophagosomal membrane, that is cleaved (LC3-I) and lipidated (LC3-II) and can be used as a marker for autophagy (41).”
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Autophagy-deficient mice develop multiple liver tumors
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“It has been shown that a lack of essential autophagy genes, such as Atg5 and Atg7, leads to the formation of p62-positive aggregates and accumulation of ubiquitin inclusions in the liver (44, 52).”
BackgroundDysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer
Singh, A., Misra, V., Thimmulappa, R. K., Lee, H., Ames, S., Hoque, M. O., Herman, J. G., Baylin, S. B., Sidransky, D., Gabrielson, E., et al. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030420 · Cited by 1,060
Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer
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Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism
Ren, D., Villeneuve, N. F., Jiang, T., Wu, T., Lau, A., Toppin, H. A., & Zhang, D. D. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014275108 · Cited by 673
Self-citationHigh Levels of Nrf2 Determine Chemoresistance in Type II Endometrial Cancer
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Cited by
NRF2 and the Hallmarks of Cancer
Rojo de la Vega, M., Chapman, E., & Zhang, D. D. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.022 · Cited by 1,672
Self-citationTebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., Dinkova-Kostova, A. T., & Hayes, J. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.021 · Cited by 837
Oxidative stress response and Nrf2 signaling in aging
Zhang, H., Davies, K. J. A., & Forman, H. J. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.05.036 · Cited by 804
The Dual Roles of NRF2 in Cancer
Menegon, S., Columbano, A., & Giordano, S. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.05.002 · Cited by 633
Thirty years of NRF2: advances and therapeutic challenges.
Zhang, D. D. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01145-0 · Cited by 282
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Metadata
- Authors
- Lau, A., Zheng, Y., Tao, S., Wang, H., Whitman, S. A., White, E., & Zhang, D. D.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2013-06
- Volume
- 33
- Issue
- 12
- Pages
- 2436-2446
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2133377747
- Cited by
- 229
- References
- 12
- FWCI
- 7.67
- Type
- journal article
- Language
- en
- Open access
- green
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