<p>Correlation of NRF2 and progesterone receptor and its effects on ovarian cancer biology</p>

Abstract

Purpose: This study aimed to investigate the potential prognostic impact of nuclear factor erythroid 2-related factor 2 (NRF2) and progesterone receptor A (PRA)/progesterone receptor B (PRB) in ovarian cancer patients which might be the rationale for putative new treatment strategies. Patients and methods: The presence of NRF2 and PRA/PRB was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC). Staining of NRF2 and PRA/ PRB was rated using the semi-quantitative immunoreactive score (IR score, Remmele's score) and correlated to clinical and pathological data. NRF2 and PRA/PRB expression were compared with respect to the overall survival (OS). Results: NRF2 staining was different in both, the cytoplasm and nucleus between the histological subtypes (p=0.001 and p=0.02, respectively). There was a significant difference in the PRA expression comparing all histological subtypes (p=0.02). Histological subtypes showed no significant differences in the PRB expression. A strong correlation of cytoplasmic NRF2 and PRA expression was detected (cc=0.247, p=0.003) as well as of cytoplasmic NRF2 and PRB expression (cc=0.25, p=0.003), confirmed by immunofluorescence double staining. Cytoplasmic NRF2 expression was associated with a longer OS (median 50.6 vs 32.5 months; p=0.1) as it was seen for PRA expression (median 63.4 vs 33.1 months; p=0.08), although not statistically significant. In addition, high PRB expression (median 80.4 vs 32.5 months; p=0.04) and concurrent expression of cytoplasmic NRF2 and PRA were associated with a significantly longer OS (median 109.7 vs 30.6 months; p=0.02). The same relationship was also noted for NRF2 and PRB with improved OS for patients expressing both cytoplasmic NRF2 and PRB (median 153.5 vs 30.6 months; p=0.009). Silencing of NFE2L2 induced higher mRNA expression of PGR in the cancer cell line OVCAR3 (p>0.05) confirming genetic interactions of NRF2 and PR. Conclusion: In this study, the combination of cytoplasmic NRF2 and high PRA/PRB expression was demonstrated to be associated with improved overall survival in ovarian cancer patients. Further understanding of interactions within the NRF2/AKR1C1/PR pathway could open new additional therapeutic approaches.

The Interaction of lncRNA XLOC-2222497, AKR1C1, and Progesterone in Porcine Endometrium and Pregnancy

“…AKR1C1 belongs to the aldo-keto reductase (AKR) superfamily of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidoreductases [48,49] and has a major role in progesterone metabolism [40,47,50]. Moreover, AKR1C1 can bind to the promoter region of the progesterone receptor and hereby decreases receptor activity [51]. AKR1C1 is expressed ubiquitously [52,53].…”

Targeting Nrf2 may reverse the drug resistance in ovarian cancer

“…A clinical study has indicated that high cytoplasmic Nrf2 expression (the inactivated form of Nrf2 ) in serous carcinoma subtypes is associated with longer survival (p < 0.05), which appears to correlate with high ERα expression (p < 0.05) [ 42 ]. The same team found that Nrf2 expression in the cytoplasm was positively correlated with PR expression (p < 0.05) [ 43 ]. Furthermore, a retrospective study of the relationship between Nrf2 expression and clinical prognosis in 108 patients with different subtypes of OC showed that a high expression of Nrf2 in OC indicates short DFS (HR: 2.084; 95% CI: 1.229–3.536) and OS (HR: 2.487; 95% CI: 1.443–4.286) [ 44 ].…”

“…Chen et al argued that knockdown of Nrf2 in the SKVO3 cell line increased the production of ROS induced by cisplatin by increasing the phosphorylation level of p38-JNK .This subsequently led to elevation of ATF2 levels, followed by decreased expression of AKR1C1 ,which is involved in apoptosis, ultimately promoting the sensitivity of OC to cisplatin [ 53 ]. It was recently reported that activation of Nrf2 promotes activation of its downstream gene AKR1C1 , which converts progesterone to an inactive form and promotes platinum resistance in ovarian cancer, while metformin reverses this process by increasing PR expression [ 54 ]. Mechanistically, Sun et al found that SIRT5 contributes to the cisplatin resistance of OC by inhibiting cisplatin-mediated DNA damage via ROS through Nrf2 pathway modulation [ 55 ].…”

Effects of chitooligosaccharide-zinc on mice ovarian function in premature ovarian failure via regulating the sestrin2/nrf2 signaling pathway

“…Studies have indicated that NRF2 is mainly regulated by Keap1 [31], and that NRF2 plays an important role in regulating ovarian dysfunction and treating ovarian cancer [32][33][34][35]. Further studies have clarify that SESN2 could both directly and indirectly participate in the regulation of NRF2 in the process of metabolism [19,36].…”