Nuclear factor erythroid 2-related factor 2 enhances carcinogenesis by suppressing apoptosis and promoting autophagy in nickel-transformed cells.
Nickel-containing compounds are widely used in industry. Nickel is a known human carcinogen that primarily affects the lungs. Proposed mechanisms of nickel-induced carcinogenesis include disruption of cellular iron homeostasis, generation of reactive oxygen species (ROS), and induction of hypoxia signaling. However, the precise molecular mechanisms of nickel-induced malignant transformation and tumor development remain unclear. This study shows that the transcription factor Nrf2 is highly expressed in lung tumor tissue and in nickel-transformed human lung bronchial epithelial BEAS-2B cells (NiT cells). Additionally, constitutively high levels of Nrf2 play a critical role in apoptosis resistance in NiT cells. Basal ROS levels were extremely low in NiT cells and were correlated with elevated expression levels of both antioxidant enzymes (e.g.catalase and superoxide dismutases) and antiapoptotic proteins (e.g.Bcl-2 and Bcl-xL). These processes are tightly controlled by Nrf2. Autophagy inhibition, induced pharmacologically or genetically, enhanced Ni2+-induced apoptosis, indicating that the induction of autophagy is the cause of apoptosis resistance in NiT cells. Using similar approaches, we show that in NiT cells the inhibition of apoptosis decreases autophagy. We have shown that Stat3, which is up-regulated by Nrf2, controls autophagy induction in NiT cells. Colony formation and tumor growth were significantly attenuated by knockdown of Nrf2 or Bcl-2. Taken together, this study demonstrates that in NiT cells constitutively high Nrf2 expression inhibits apoptosis by up-regulating antioxidant enzymes and antiapoptotic proteins to increase autophagy via Stat3 signaling. These findings indicate that the Nrf2-mediated suppression of apoptosis and promotion of autophagy contribute to nickel-induced transformation and tumorigenesis.
Center for Research on Environmental Disease; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305; National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, South Korea. Electronic address: sounagi@gist.ac.kr.
Young-Ok
YO
Son
Center for Research on Environmental Disease; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
Poyil
P
Pratheeshkumar
Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
Sasidharan Padmaja
SP
Divya
Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
Zhuo
Z
Zhang
Center for Research on Environmental Disease; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305. Electronic address: xshi5@email.uky.edu.
Xianglin
X
Shi
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009532:Nickel / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
C000595707:BCL2 protein, human; C494811:BCL2L1 protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051020:bcl-X Protein; D009532:Nickel; D002374:Catalase; D013482:Superoxide Dismutase
apoptosis; autophagy; carcinogenesis; nickel; nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2); transformed cells