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

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.