Role of NRF2 in Ovarian Cancer

Abstract

Among gynaecologic malignancies, ovarian cancer is one of the most dangerous, with a high fatality rate and relapse due to the occurrence of chemoresistance. Many researchers demonstrated that oxidative stress is involved in tumour occurrence, growth and development. Nuclear factor erythroid 2-related factor 2 (NRF2) is an important transcription factor, playing an important role in protecting against oxidative damage. Increased levels of Reactive Oxygen Species (ROS) activate NRF2 signalling, inducing the expression of antioxidant enzymes, such as haem oxygenase (HO-1), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), that protect cells against oxidative stress. However, NRF2 activation in cancer cells is responsible for the development of chemoresistance, inactivating drug-mediated oxidative stress that normally leads to cancer cells' death. In this review, we report evidence from the literature describing the effect of NRF2 on ovarian cancer, with a focus on its function in drug resistance, NRF2 natural and synthetic modulators and its protective function in normal ovarian preservation.

Keywords: NRF2; chemotherapy; cisplatin; ovarian cancer; ovarian preservation.

Figure 1

Schematic representation of NRF2 regulation. Normally, NRF2 is directly bound to the KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex that targets NRF2 for proteasomal degradation. Under oxidant stimuli, ROS oxidate the cysteine residues of KEAP1 leading to a conformation change in KEAP1 that causes the inhibition of NRF2 ubiquitination and its translocation into the nucleus with consequent binding to the ARE regions of antioxidant genes (NQO1, GST, HO-1, etc.). KEAP1 = Kelch-like ECH Associated Protein 1; CUL3 = Cullin 3; RBX1 = RING-box protein 1.

Figure 2

Schematic representation of NRF2 modulation. Vitamin C, SB216763, resveratrol, melatonin, epigallocatechin-3-gallate and theaflavins increase NRF2 expression in ovarian cells improving their response to oxidant agents. In ovarian cancer cells, increased levels of miR-181d, Lin-H19, p62, SIRT5, PUMA and KEAP1/CUL3/RBX1 alterations lead to an increase in NRF2 expression. However, decreased levels of NRF2 lead to an increased expression of ERα, PGR, SLC40A1, miR-206 and decreased expression of CD99, ErbB2 and AKR1C1-3. In addition, NRF2 indirectly decreases c-MET and EGFR expression by increasing miR-206 levels.