Oxidative Stress and Cancer Heterogeneity Orchestrate NRF2 Roles Relevant for Therapy Response

Abstract

Oxidative stress and its end-products, such as 4- hydroxynonenal (HNE), initiate activation of the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)/KEAP1 signaling pathway that plays a crucial role in the maintenance of cellular redox homeostasis. However, an involvement of 4-HNE and NRF2 in processes associated with the initiation of cancer, its progression, and response to therapy includes numerous, highly complex events. They occur through interactions between cancer and stromal cells. These events are dependent on many cell-type specific features. They start with the extent of NRF2 binding to its cytoplasmic repressor, KEAP1, and extend to the permissiveness of chromatin for transcription of ARE-containing genes that are NRF2 targets. This review will explore epigenetic molecular mechanisms of NRF2 transcription through the specific molecular anatomy of its promoter. It will explain the role of NRF2 in cancer stem cells, with respect to cancer therapy resistance. Additionally, it also discusses NRF2 involvement at the cross-roads of communication between tumor associated inflammatory and stromal cells, which is also an important factor involved in the response to therapy.

Resveratrol regulates inflammation and improves oxidative stress via Nrf2 signaling pathway: Therapeutic and biotechnological prospects

“…The nuclear erythroid 2-related factor 2 (NERF2) is a transcription factor with anti-inflammatory, antioxidant properties which is involved in enzyme biosynthesis and biotransformation of lipids and carbohydrates (Besednova et al, 2022). Nrf2 plays a key role in maintaining homeostasis; therefore, protect organs especially cardiopulmonary, renal, and nervous systems against cancer and other disorders caused by increased oxidative stress (Gall Trošelj et al, 2022;Huang et al, 2022;Hybertson, Gao, & McCord, 2022;Wang, Long, Lin, Wang, & Wang, 2022;Zhu et al, 2022). Thus, the potential interaction of resveratrol with the Nrf2 pathway in preventing obesity, diabetes, and cancer should be taken into consideration (Kay et al, 2015;Das & Banik, 2022;Lynn, Park, Ogunwale, & Acquaah-Mensah, 2022;Malaguarnera et al, 2018;Meng, Zhou, Zhao, Gan, & Li, 2020;Nakata, Takahashi, & Inoue, 2012;Piotrowska, Kucinska, & Murias, 2012;Shahidi & Ambigaipalan, 2015;Talebi, Talebi, Farkhondeh, & Samarghandian, 2022;Thiel & Rössler, 2017;Wen, Zhang, Yang, Elias, & Man, 2020).…”

The 4-Hydroxynonenal–Protein Adducts and Their Biological Relevance: Are Some Proteins Preferred Targets?

“…The likely mechanism involves 4-HNE adduction of KEAP1 [ 134 ], which disrupts the NRF2 binding to KEAP1 and subsequent proteasomal degradation of NRF2. Instead, the accumulated cytoplasmic NRF2 translocates to the nucleus initiating the expression of more than 200 genes containing the antioxidant response element (ARE) in their promoters [ 135 ]; TrxR1 is one of them [ 136 ]. In fact, Gao et al linked a deficiency of solute carrier family 27 member 5 (SLC27A5/FATP5), which leads to an increase in PUFA, to accumulation of HNE adducts and activation of the NRF2/TrxR1 axis to treatment resistance in hepatocellular carcinoma.…”

Moderate red wine intake and cardiovascular health protection: a literature review

“…81 Nrf2 regulates homeostasis and hence protects organs, particularly the cardiac, renal, and neurological systems, from diseases caused by excessive oxidative stress. [82][83][84][85][86] Flavonoids, including the ones present in red wine, are among the stronger activator of this transcription factor. According to Cheng et al, resveratrol (3,4′,5-trihydroxytrans-stilbene), a natural polyphenol found in red wine, activates Nrf2 by altering the cellular redox state.…”