Nrf2/p62 signaling in apoptosis resistance and its role in cadmium-induced carcinogenesis

Young Ok Son, Poyil Pratheeshkumar, Ram Vinod Roy, John Andrew Hitron, Lei Wang, Zhuo Zhang, Xianglin Shi

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

The cadmium-transformed human lung bronchial epithelial BEAS-2B cells exhibit a property of apoptosis resistance as compared with normal non-transformed BEAS-2B cells. The level of basal reactive oxygen species (ROS) is extremely low in transformed cells in correlation with elevated expressions of both antioxidant enzymes (catalase, SOD1, and SOD2) and antiapoptotic proteins (Bcl-2/Bcl-xL). Moreover, Nrf2 and p62 are highly expressed in these transformed cells. The knockdown of Nrf2 or p62 by siRNA enhances ROS levels and cadmium-induced apoptosis. The binding activities of Nrf2 on the antioxidant response element promoter regions of p62/Bcl-2/Bcl-xL were dramatically increased in the cadmium-exposed transformed cells. Cadmium exposure increased the formation of LC3-II and the frequency of GFP-LC3 punctal cells in nontransformed BEAS-2B cells, whereas these increases are not shown in transformed cells, an indication of autophagy deficiency of transformed cells. Furthermore, the expression levels of Nrf2 and p62 are dramatically increased during chronic long term exposure to cadmium in the BEAS-2B cells as well as antiapoptotic proteins and antioxidant enzymes. These proteins are overexpressed in the tumor tissues derived from xenograft mouse models. Moreover, the colony growth is significantly attenuated in the transformed cells by siRNA transfection specific for Nrf2 or p62. Taken together, this study demonstrates that cadmium-transformed cells have acquired autophagy deficiency, leading to constitutive p62 and Nrf2 overexpression. These overexpressions up-regulate the antioxidant proteins catalase and SOD and the antiapoptotic proteins Bcl-2 and Bcl-xL. The final consequences are decrease inROSgeneration, apoptotic resistance, and increased cell survival, proliferation, and tumorigenesis.

Original languageEnglish
Pages (from-to)28660-28675
Number of pages16
JournalJournal of Biological Chemistry
Volume289
Issue number41
DOIs
StatePublished - Oct 10 2014

Bibliographical note

Publisher Copyright:
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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