Son Young-Ok, Pratheeshkumar Poyil, Divya Sasidharan Padmaja, Zhang Zhuo, Shi Xianglin
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.
Center for Research on Environmental Disease; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305.
J Biol Chem. 2017 May 19;292(20):8315-8330. doi: 10.1074/jbc.M116.773986. Epub 2017 Mar 22.
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 ( catalase and superoxide dismutases) and antiapoptotic proteins ( Bcl-2 and Bcl-xL). These processes are tightly controlled by Nrf2. Autophagy inhibition, induced pharmacologically or genetically, enhanced Ni-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.
含镍化合物在工业中广泛使用。镍是一种已知的人类致癌物，主要影响肺部。镍诱导致癌的机制包括破坏细胞铁稳态、产生活性氧（ROS）以及诱导缺氧信号。然而，镍诱导恶性转化和肿瘤发展的确切分子机制仍不清楚。本研究表明，转录因子Nrf2在肺肿瘤组织和镍转化的人肺支气管上皮BEAS-2B细胞（NiT细胞）中高表达。此外，持续高水平的Nrf2在NiT细胞的抗凋亡中起关键作用。NiT细胞中的基础ROS水平极低，且与抗氧化酶（过氧化氢酶和超氧化物歧化酶）和抗凋亡蛋白（Bcl-2和Bcl-xL）的表达水平升高相关。这些过程由Nrf2严格控制。通过药理学或遗传学方法诱导的自噬抑制增强了镍诱导的凋亡，表明自噬的诱导是NiT细胞抗凋亡的原因。使用类似方法，我们表明在NiT细胞中抑制凋亡会降低自噬。我们已经表明，由Nrf2上调的Stat3控制NiT细胞中的自噬诱导。通过敲低Nrf2或Bcl-2，集落形成和肿瘤生长显著减弱。综上所述，本研究表明，在NiT细胞中，持续高表达的Nrf2通过上调抗氧化酶和抗凋亡蛋白，经由Stat3信号传导增加自噬来抑制凋亡。这些发现表明，Nrf2介导的凋亡抑制和自噬促进作用有助于镍诱导的细胞转化和肿瘤发生。
