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Nrf2/p62 signaling in apoptosis resistance and its role in cadmium-induced carcinogenesis
Young-Ok Son1, Poyil Pratheeshkumar1, Ram Vinod Roy1
1From the Center for Research on Environmental Disease and the Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
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 non-transformed 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 in ROS generation, apoptotic resistance, and increased cell survival, proliferation, and tumorigenesis.
Insights
Cadmium-transformed lung cells resist apoptosis by overexpressing Nrf2 and p62, which boosts antioxidant and antiapoptotic proteins. This leads to reduced reactive oxygen species (ROS) and increased cell survival and tumor growth.
Area of Science:
- Cell Biology
- Toxicology
- Cancer Research
Background:
- Cadmium exposure induces transformation in human lung bronchial epithelial BEAS-2B cells.
- Transformed cells display resistance to apoptosis compared to normal cells.
- Basal reactive oxygen species (ROS) levels are low in transformed cells, correlating with elevated antioxidant and antiapoptotic proteins.
Purpose of the Study:
- To investigate the mechanisms underlying cadmium-induced apoptosis resistance in BEAS-2B cells.
- To elucidate the roles of Nrf2, p62, and autophagy in cadmium transformation and tumorigenesis.
- To explore the therapeutic potential of targeting Nrf2 and p62.
Main Methods:
- Cell culture and transformation using cadmium.
- siRNA-mediated knockdown of Nrf2 and p62.
- Measurement of ROS levels.
- Western blotting for antioxidant and antiapoptotic proteins.
- Analysis of autophagy markers (LC3-II, GFP-LC3).
- Chromatin immunoprecipitation assays.
- Xenograft mouse models.
Main Results:
- Cadmium-transformed cells exhibit high Nrf2 and p62 expression, increased antioxidant enzymes (catalase, SOD1/2), and antiapoptotic proteins (Bcl-2/Bcl-xL).
- Nrf2/p62 knockdown increases ROS and apoptosis, while Nrf2 binding to target gene promoters is enhanced.
- Autophagy is deficient in transformed cells, indicated by lack of LC3-II and GFP-LC3 puncta formation.
- Nrf2 and p62 overexpression is sustained during chronic cadmium exposure and observed in xenograft tumor tissues.
- Knockdown of Nrf2 or p62 attenuates colony growth in transformed cells.
Conclusions:
- Cadmium transformation leads to autophagy deficiency, resulting in constitutive overexpression of p62 and Nrf2.
- This overexpression upregulates antioxidant and antiapoptotic proteins, decreasing ROS and promoting apoptosis resistance.
- The findings highlight a critical pathway involving autophagy, Nrf2, and p62 in cadmium-induced cell survival, proliferation, and tumorigenesis.
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