Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane

Yuting Wang, Ardhendu Kumar Mandal, Young O.K. Son, Poyil Pratheeshkumar, James T.F. Wise, Lei Wang, Zhuo Zhang, Xianglin Shi, Zhimin Chen

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

Environmental and occupational exposures to cadmium increase the risk of various cancers, including lung cancer. The carcinogenic mechanism of cadmium, including its prevention remains to be investigated. Using fluorescence and electron spin resonance spin trapping, the present study shows that in immortalized lung cells (BEAS-2BR cells), exposure cadmium generated reactive oxygen species (ROS). Through ROS generation, cadmium increased the protein level of TNF-α which activated NF-κB and its target protein COX-2, creating an inflammatory microenvironment. As measured by anchorage-independent colony formation assay, cadmium induced malignant cell transformation. Inhibition of ROS by antioxidants inhibited transformation, showing that ROS were important in the mechanism of this process. The inflammatory microenvironment created by cadmium may also contribute to the mechanism of the transformation. Using tandem fluorescence protein mCherry-GFP-LC3 construct, the present study shows that cadmium-transformed cells had a property of autophagy deficiency, resulting in accumulation of autophagosomes and increased p62. This protein upregulated Nrf2, which also upregulated p62 through positive feed-back mechanism. Constitutive Nrf2 activation increased its downstream anti-apoptotic proteins, Bcl-2 and Bcl-xl, resulting in apoptosis resistance. In untransformed BEAS-2BR cells, sulforaphane, a natural compound, increased autophagy, activated Nrf2, and decreased ROS. In cadmium-transformed BEAS-2BR cells, sulforaphane restored autophagy, decreased Nrf2, and decreased apoptosis resistance. In untransformed cells, this sulforaphane induced inducible Nrf2 to decrease ROS and possibly malignant cell transformation. In cadmium-transformed cells, it decreased constitutive Nrf2 and reduced apoptosis resistance. The dual roles of sulforaphane make this natural compound a valuable agent for prevention against cadmium-induced carcinogenesis.

Original languageEnglish
Pages (from-to)23-30
Number of pages8
JournalToxicology and Applied Pharmacology
Volume353
DOIs
StatePublished - Aug 15 2018

Bibliographical note

Funding Information:
We would like to thank Hong Lin from the University of Kentucky technical and administrative support. This research was supported by National Institutes of Health [ R01ES021771 , R01ES020870 , R01ES025515 , R01ES28984 , R01ES21771 , and P30ES026529 ].

Publisher Copyright:
© 2018

Keywords

  • Autophagy deficiency
  • Cadmium
  • Carcinogenesis
  • Sulforaphane

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Fingerprint

Dive into the research topics of 'Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane'. Together they form a unique fingerprint.

Cite this