The Nrf2/HO‐1 Axis in Cancer Cell Growth and Chemoresistance

Abstract

The transcription factor, nuclear factor erythroid 2 p45-related factor 2 (Nrf2), acts as a sensor of oxidative or electrophilic stresses and plays a pivotal role in redox homeostasis. Oxidative or electrophilic agents cause a conformational change in the Nrf2 inhibitory protein Keap1 inducing the nuclear translocation of the transcription factor which, through its binding to the antioxidant/electrophilic response element (ARE/EpRE), regulates the expression of antioxidant and detoxifying genes such as heme oxygenase 1 (HO-1). Nrf2 and HO-1 are frequently upregulated in different types of tumours and correlate with tumour progression, aggressiveness, resistance to therapy, and poor prognosis. This review focuses on the Nrf2/HO-1 stress response mechanism as a promising target for anticancer treatment which is able to overcome resistance to therapies.

The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells

“…Nrf2 and downstream target genes serve a pivotal role in cellular redox homeostasis, elimination of ROS and xenobiotic metabolism (5). Persistent Nrf2-mediated antioxidant responses promote malignant progression, development of acquired apoptotic resistance and chemo-resistance in cancer cells (30,31). Therefore, the identification of stable, safe and potent Nrf2 inhibitors to decrease the antioxidant response and reduce drug metabolism in tumor cells is urgently required.…”

“…2'-7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probes were used to measure the intracellular generation of hydrogen peroxide (H 2 O 2 ) and superoxide anions (O2˙-), respectively (30). These probes are stable nonpolar compounds that readily diffuse into cells.…”

Redox signaling mediated by the gut microbiota

“…Importantly, studies into Nrf2 function exposed a plethora of cellular processes other than cytoprotection which are regulated by its signaling. These include diabetes [96], cancer cell growth and chemoresistance [97][98][99], neurodegenerative diseases [100], redox homeostasis in the aging heart [101], as well as oxidative stress and inflammatory pathways [102]. Furthermore, ROS are generated as by products during inflammation in the gut epithelia, primarily due to respiratory burst activity from phagocytes described earlier in this review.…”

Bortezomib Effects on Human Microvascular Endothelium in vitro

“…For real-time quantitative PCR (qRT-PCR), RNA was reverse-transcribed using the high capacity cDNA synthesis kit (Life Technologies, Grand Island, N.Y., USA) in accordance with the manufacturer's instructions. Briefly, RT reactions were assembled in a total volume of 20 For protein expression analysis, total cellular extracts were prepared using a lysis buffer supplemented with the protease inhibitor cocktail and subjected to Western blot analysis with antibodies for specific detection of HO-1 and COX-2 and enhanced chemiluminescence-based signal detection on immunoblot as described previously [9] . The preparation of cytoplasmic and nuclear extracts from bortezomib-treated and corresponding vehicletreated HMECs was carried out employing an established protocol [9] .…”