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

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 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.

NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells

“…A recent study has suggested that NRF2 upregulates the transcription of Stat3 as one of the target genes (45). However, this scenario does not seem applicable to our result, because STAT3 phosphorylation is promoted without any increase in the amount of total STAT3 protein in Keap1-deficient HSPCs.…”

Complex interplay between autophagy and oxidative stress in the development of pulmonary disease

“…Thus, the disruption of the Nrf2-Keap1 pathway can suppress autophagy while autophagy deficiency leads to the overexpression of the Nrf2-Keap1 pathway. The regulation and co-ordination of Keap1–Nrf2 and the autophagy pathway are essential for cell growth, differentiation, redox signaling and survival, has been addressed in several studies [ 205 , 206 ]. A recent investigation showed that during prolonged exposure of oxidative stress, using tert-butyl hydroperoxide (TBHP), Nrf2 negatively regulates autophagy through the down-regulation of AMPK [ 207 ].…”

Nrf2 positively regulates autophagy antioxidant response in human bronchial epithelial cells exposed to diesel exhaust particles

“…Son et al 32 used nickel-transformed BEAS-2B cells and showed increased LC3II levels and overexpression of Stat3, a protein with a promoter region that has an ARE binding site. When Stat3 levels were suppressed, a reduction in LC3II level was found, while Nrf2 suppression resulted in depletion of Stat3, indicating that Nrf2 exerts an influence on the sensitivity of autophagy.…”