Targeting Nrf2-Mediated Oxidative Stress Response Signaling Pathways as New Therapeutic Strategy for Pituitary Adenomas

Abstract

Oxidative stress and oxidative damage are the common pathophysiological characteristics in pituitary adenomas (PAs), which have been confirmed with many omics studies in PA tissues and cell/animal experimental studies. Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), the core of oxidative stress response, is an oxidative stress sensor. Nrf2 is synthesized and regulated by multiple factors, including Keap1, ERK1/2, ERK5, JNK1/2, p38 MAPK, PKC, PI3K/AKT, and ER stress, in the cytoplasm. Under the oxidative stress status, Nrf2 quickly translocates from cytoplasm into the nucleus and binds to antioxidant response element /electrophile responsive element to initiate the expressions of antioxidant genes, phases I and II metabolizing enzymes, phase III detoxifying genes, chaperone/stress response genes, and ubiquitination/proteasomal degradation proteins. Many Nrf2 or Keap1 inhibitors have been reported as potential anticancer agents for different cancers. However, Nrf2 inhibitors have not been studied as potential anticancer agents for PAs. We recommend the emphasis on in-depth studies of Nrf2 signaling and potential therapeutic agents targeting Nrf2 signaling pathways as new therapeutic strategies for PAs. Also, the use of Nrf2 inhibitors targeting Nrf2 signaling in combination with ERK inhibitors plus p38 activators or JNK activators targeting MAPK signaling pathways, or drugs targeting mitochondrial dysfunction pathway might produce better anti-tumor effects on PAs. This perspective article reviews the advances in oxidative stress and Nrf2-mediated oxidative stress response signaling pathways in pituitary tumorigenesis, and the potential of targeting Nrf2 signaling pathways as a new therapeutic strategy for PAs.

Gastrodin inhibits high glucose‑induced inflammation, oxidative stress and apoptosis in podocytes by activating the AMPK/Nrf2 signaling pathway

“…In the present study, gastrodin upregulated the phosphorylation levels of AMPK, Nrf2 and the expression of HO-1, which was consistent with the previous study aforementioned. Previous studies also reported that AMPK and Nrf2 can mediate fatty acid oxidation and reduce oxidative stress, respectively (47,48). The activation of AMPK/Nrf2 signaling was previously found to improve lipid metabolism and attenuated oxidative stress in renal tissues of mice with type 2 diabetes-induced nephropathy (25,49).…”

Recent findings on the cellular and molecular mechanisms of action of novel food-derived antihypertensive peptides

“…However, when the system is oxidatively-stressed, the Nrf2 from the cytoplasm is translocated to the nucleus, where it binds to the ARE of the gene coding for antioxidant proteins, activating a cascade of reaction which help to curb the oxidative pressure on the cells ( Saha, Buttari, Panieri, Profumo, & Saso, 2020 ). Studies have shown with consensus evidence that decrease in Nrf2 activities invariably contributes to oxidative stress and cardiovascular diseases such as hypertension ( Serafini et al, 2020 , Zhan et al, 2021 ). Considering that some antioxidant peptides also exhibit antihypertensive properties, and that oxidative stress is implicated in hypertension ( Griendling et al, 2021 ), the investigation of Keap-1/Nrf2 signaling pathway (the activation or upregulation the expression and translocation of nuclear Nrf2) and gene expression of antioxidant enzyme activities in peptide-treated SHR is recommended for future studies.…”

Architects of Pituitary Tumour Growth

“…In addition, mitochondrial proteins can regulate numerous signalling pathway networks and cellular behaviours, with this organelle being involved in an extensive range of diseases, including tumorigenesis (116). Molecular network studies have revealed that mitochondrial dysfunction, oxidative stress and mitochondria-mediated ROS-mitogen-activated protein kinase (MAPK) signalling abnormality are significantly associated with the pathogenesis of PitNETs (69,70,72,(117)(118)(119)(120).…”

“…Furthermore, mitochondrial dysfunction has been described showing morphological and functional changes, such as bigger mitochondria with irregular swelling and fragmented cristaes ( 124 ). An activation of the nuclear factor erythroid 2 like 2 (Nrf2) pathways, a main regulator of oxidative stress response along with oxidative damage signal reduction, have been reported during PitNET development, which might provide cellular survival advantages ( 120 , 124 ). Indeed, elevated mitophagy and mitochondrial dysfunction may favour resistance to chemotherapy in the pituitary GH3 cell line ( 131 ).…”