Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis

Abstract

Cancer cells are hallmarked by high proliferation and imbalanced redox consumption and signaling. Various oncogenic pathways such as proliferation and evading cell death converge on redox-dependent signaling processes. Nrf2 is a key regulator in these redox-dependent events and operates in cytoprotection, drug metabolism and malignant progression in cancer cells. Here, we show that patients with primary malignant brain tumors (glioblastomas, WHO °IV gliomas, GBM) have a devastating outcome and overall reduced survival when Nrf2 levels are upregulated. Nrf2 overexpression or Keap1 knockdown in glioma cells accelerate proliferation and oncogenic transformation. Further, activation of the Nrf2-Keap1 signaling upregulates xCT (aka SLC7A11 or system Xc−) and amplifies glutamate secretion thereby impacting on the tumor microenvironment. Moreover, both fostered Nrf2 expression and conversely Keap1 inhibition promote resistance to ferroptosis. Altogether, the Nrf2-Keap1 pathway operates as a switch for malignancy in gliomas promoting cell proliferation and resistance to cell death processes such as ferroptosis. Our data demonstrate that the Nrf2-Keap1 pathway is critical for cancer cell growth and operates on xCT. Nrf2 presents the Achilles’ heel of cancer cells and thus provides a valid therapeutic target for sensitizing cancer for chemotherapeutics.

The Carcinogenic Agent Diethylnitrosamine Induces Early Oxidative Stress, Inflammation and Proliferation in Rat Liver, Stomach and Colon: Protective Effect of Ginger Extract

“…Those molecular targets of ginger indicate that it may have the potential for preventing and treating GI cancer (Prasad and Tyagi, 2015b). Though the notion that Nrf2 inducers and/or Keap-1 suppressors may serve as promoters of cancer cell proliferation with increased resistance to ferroptosis cell death (Fan et al, 2017); ginger extract exerted an Nrf-2-inducing activity with concurrent inhibition of alpha-feto protein, proliferation marker, in all examined tissues and decline in oxidative and inflammatory markers, thus contributing to its chemoprevention activity probably via mechanism involving Nrf2/Keap1/ARE pathway. Therefore, further molecular investigation is warranted to outline ginger antioxidant/anti-inflammatory/anti-proliferative crosstalk mechanism.…”

Ferroptosis and Its Potential Role in Human Diseases

“…Under normoxic cellular conditions, Nrf2 is bound by Kelch-like ECH-associated protein 1 (Keap1) and persists in an inactivated status through ubiquitination and degradation in the proteasome (Reisman et al, 2009). Upon oxidative or electrophilic stress, Nrf2 becomes unleashed from the Keap1 protein binding and translocates to the nucleus (Fan et al, 2017). In the nucleus, Nrf2 transcripts antioxidant responsive element (ARE)-dependent genes in order to balance oxidative mediators and maintain cellular redox homeostasis (Hayes and Dinkova-Kostova, 2014).…”

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…The activity of Nrf2 is strictly regulated by Kelch-like ECH-related protein 1 (Keap1); Keap1 not only passively isolates Nrf2 from the cytoplasm but also plays an active role in targeting Nrf2 for ubiquitination and proteasome degradation (Zhang et al, 2004;Furukawa and Xiong, 2005). Nrf2 can directly or indirectly regulate GPX4 protein content (Hayes and Dinkova-Kostova, 2014;Fan et al, 2017;Dodson et al, 2019;Zhang et al, 2019), intracellular free iron content (Agyeman et al, 2012;Sun et al, 2016b;Shin et al, 2018), mitochondrial function (Merry and Ristow, 2016;Navarro et al, 2017), nicotinamide adenine dinucleotide hydro-phosphoric acid (NAPDH) regeneration (Abdalkader et al, 2018), etc., thereby regulating ferroptosis process. Of note, many studies found that Nrf2 is expressed in the central nervous system (CNS), neurons, astrocytes, leukocytes, and microglia (Tanaka et al, 2011;Dang et al, 2012;Sandberg et al, 2014), and numerous evidence suggests that Nrf2 plays an important role in the development and treatment of neurodegenerative diseases Deng et al, 2019;Jang et al, 2019;Pachón-Angona et al, 2019;Wei et al, 2019).…”