Nuclear factor erythroid 2-related factor 2 enhances carcinogenesis by suppressing apoptosis and promoting autophagy in nickel-transformed cells

Young Ok Son, Poyil Pratheeshkumar, Sasidharan Padmaja Divya, Zhuo Zhang, Xianglin Shi

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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 nickelinduced malignant transformation and tumor development remain unclear. This study shows that the transcription factor Nrf2 is highly expressed in lung tumor tissue and in nickeltransformed 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.Wehave 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 upregulating 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.

Original languageEnglish
Pages (from-to)8315-8330
Number of pages16
JournalJournal of Biological Chemistry
Volume292
Issue number20
DOIs
StatePublished - May 19 2017

Bibliographical note

Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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