Nrf2 and Notch Signaling in Lung Cancer: Near the Crossroad

Abstract

The transcription factor Nrf2 (NF-E2 related factor 2) is a master regulator of the cell antioxidant response associated with tumor growth and resistance to cytotoxic treatments. In particular, Nrf2 induces upregulation of cytoprotective genes by interacting with the closely situated AREs (Antioxidant Response Elements) in response to endogenous or exogenous stress stimuli and takes part to several oncogenic signaling pathways. Among these, the crosstalk with Notch pathway has been shown to enhance cytoprotection and maintenance of cellular homeostasis, tissue organization by modulating cell proliferation kinetics, and stem cell self-renewal in several organs. The role of Notch and Nrf2 related pathways in tumorigenesis is highly variable and when they are both abnormally activated they can synergistically cause neoplastic proliferation by promoting cell survival, differentiation, invasion, and metastases. NFE2L2, KEAP1, and NOTCH genes family appear in the list of significantly mutated genes in tumors in both combined and individual sets, supporting the crucial role that the aberrant Nrf2-Notch crosstalk might have in cancerogenesis. In this review, we summarize current knowledge about the alterations of Nrf2 and Notch pathways and their reciprocal transcriptional regulation throughout tumorigenesis and progression of lung tumors, supporting the potentiality of putative biomarkers and therapeutic targets.

Nrf2 regulates cellular behaviors and Notch signaling in oral squamous cell carcinoma cells

“…Since recent literature suggested a cross-talk between Nrf2 and Notch signaling [10,22], we then examined potential regulation of Notch signaling by Nrf2 in vitro and in vivo . Our data clearly showed that expression of both NICD1 and Hes1 in oral squamous epithelial cells were regulated by Nrf2 (Fig.…”

“…On the other hand, Nrf2 activation is known to promote cancer cell survival, suppress apoptosis, and cause chemoradioresistance [8,9]. Nrf2 activation plays an oncogenic role in various cancers including head and neck cancer [10]. However, the functional roles of Nrf2 in OSCC remain unclear.…”

“…Notch maintains stem cell and/or transit amplifying cells in an undifferentiated status. Interestingly, Nrf2 signaling and Notch signaling mutually regulate each other as shown by that Notch1 is an Nrf2 target gene and Nrf2 is a downstream gene regulated by Notch signaling [10]. Therefore it is possible that Nrf2 may promote cellular behaviors of OSCC through Notch signaling.…”

Tocotrienol-rich mixture inhibits cell proliferation and induces apoptosis via down-regulation of the Notch-1/NF-κB pathways in NSCLC cells

“…16 Additionally, Notch-1 gene mutations are more frequently recognized than other Notch receptor genes in tumors with Notch sequencing data. 17 Taken together, these reports suggest that modification of Notch-1 signaling may be a preferred beneficial therapeutic target for NSCLC. Notch-1 has been reported to cross talk with NF-kB, which plays a major role in numerous biological processes, including cell proliferation, cell death, inflammation, apoptosis regulation, and immune response in cancer cell transformation and development.…”

Role of uL3 in Multidrug Resistance in p53-Mutated Lung Cancer Cells

“…To date, it has been demonstrated that the increase of GSH concentration or GST expression are linked to chemoresistance pathways in human breast cancer cells [32]. Pathways involved in GSH production and regeneration are controlled by Nrf2, a crucial regulator of the expression of different genes involved in oxidative stress response and drug resistance [33,34,35]. In order to evaluate the role of the GSH/GST system in rCalu-6 cells, we monitored the levels of intracellular GSH in these cells and in its parent cell line.…”