Sustained NRF2 activation in hereditary leiomyomatosis and renal cell cancer (HLRCC) and in hereditary tyrosinemia type 1 (HT1)

Abstract

The nuclear erythroid 2-like 2 transcription factor (NRF2), is a major regulator of cellular redox balance. Although NRF2 activation is generally regarded as beneficial to human health, recent studies have identified that sustained NRF2 activation is over-represented in many cancers. This raises the question regarding the role of NRF2 activation in the development and progression of those cancers. This review focuses on the mechanisms and the effects of NRF2 activation in two hereditary cancer predisposition syndromes: hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary tyrosinemia type 1 (HT1). Because the cancer initiating mutations in these hereditary syndromes are well defined, they offer a unique opportunity to explore the roles of NRF2 activation in the early stages of carcinogenesis. Over the years, a variety of approaches have been utilized to study the biology of HLRCC and HT1. In HLRCC, in vitro studies have demonstrated the importance of NRF2 activation in sustaining cancer cell proliferation. In the mouse model of HT1 however, NRF2 activation seems to protect cells from malignant transformation. In both HT1 and HLRCC, NRF2 activation promotes the clearance of electrophilic metabolites, enabling cells to survive cancer-initiating mutations. Biological insights gained from the hereditary syndromes' studies may shed light on to the roles of NRF2 activation in sporadic tumours.

The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic

“…Activation of the Nrf2 pathway by phytochemicals may be of benefit in the prevention of cancer and absence of Nrf2 increases susceptibility of cells to cancer. However, on the flip side, excessive sustained Nrf2 activation is observed in many cancer cell types, particularly the lung, due to loss-offunction somatic mutations in Keap1 or gain-of-function 'hot spot' mutations in NFE2L2 that encodes Nrf2 [4,12]. Nrf2 can drive cell proliferation and inhibit apoptosis and enhance tumour development through metabolic reprogramming, including up-regulation of the pentose phosphate pathway.…”

“…Cancer cells also hijack the Keap1-Nrf2 pathway to enhance chemoresistance and radio-resistance. Large-scale multiomics projects in various cancer types are underway to identify mechanisms leading to increased Nrf2 activity in cancer [4,12,13].…”

GSTZ 1‐1 Deficiency Activates NRF 2/ IGF 1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone

“…Interestingly, NRF2 activation was also observed in FAH −/− mice (Marhenke et al , ), but the mechanism underlying NRF2 activation was not assessed. Sandhu predicted that FAA activates NRF2 by covalently modifying cysteine residues of KEAP1 (Sandhu et al , ). Because SA accumulated in HT1 as well, our MS/MS data suggested that SA may also contribute to NRF2 activation in FAH −/− mice via direct modification of KEAP1.…”

Therapeutic Strategies for Hereditary Kidney Cancer

“…Additionally, increased cellular glucose levels stimulate NADPH-mediated reactive oxygen species (ROS) production which can also directly stabilize HIF1 [32]. Excess HIF accumulates and results in increased transcription of multiple factors (VEGF, PDGF, GLUT, EGFR, glycolytic enzymes) which promote tumor growth and angiogenesis and support aerobic glycolysis [33,34]; 3) Excess fumarate also leads to activation of an oxidative stress response pathway mediated by NRF2, believed to be essential for cell survival in the context of redox imbalances resulting from Krebs cycle inactivation [35,36].…”