Table 2.
NRF2 cellular modulators in ovarian cancer.
| Modulator | Model Studied |
Results | Ref. |
|---|---|---|---|
| miR-181d | Ovarian tissues A2780 and A2780/DDP cells |
Increased miR-181d expression in ovarian tissues of DDP-resistant patients and in the A2780/DDP cell line. MiR-181d increases DDP resistance by downregulating OGT that represses NRF2 expression through glycosylation of KEAP1. | [40] |
| Lin-H19 | A2780 and A2780/DDP cells |
Increased expression of LIN-RECK-3, H19, LUCAT1, LINC00961 and linc-CARS2-2 in A2780/CDDP cells. Lin-H19 knockdown in A2780/CDDP cells leads to cisplatin sensitivity and reduces the expression of NQO1, GSR, G6PD, GCLC, GCLM and GSTP1. | [46] |
| p62/SQSTM1 | SKOV3 and SKOV3/CDDP cells | SKOV3/CDDP has higher levels of p62 than the cisplatin-sensitive SKOV3 cells. P62 activates KEAP1-NRF2-ARE pathway that induces the expression of antioxidant genes in SKOV3/DDP cells. | [53] |
| KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex alterations | Serous ovarian carcinomas (OVCA) patients | Almost 90% of OVCA cases shows function alterations in any components of the NRF2 inhibitory complex. Copy-number loss (CNL) is the most prominent disruption mechanism and most frequently observed in RBX1 component. High frequency of DNA and mRNA alterations of the KEAP1/CUL3/RBX1 complex leads to high levels of NRF2 in OVCA. | [60] |
| SIRT5 | SKOV-3, CAOV-3 and A2780 cells | SIRT5 levels are higher in cisplatin-resistant SKOV-3 and CAOV-3 ovarian cancer cells than in cisplatin-sensitive A2780 cells. Overexpression of SIRT5 in A2780 cells facilitates cell growth and cisplatin-resistance suppressing cisplatin-induced DNA damage by increasing NRF2 and HO-1 expression. | [56] |
| KEAP1 mutations | Epithelial ovarian cancer (EOC) patient specimens | Nuclear NRF2 is present in over half of EOC specimens with a more frequency in clear cell subtype and upregulation of NRF2 target genes. Genetic mutations of KEAP1 sequence in 29% of clear cell carcinoma samples and 8% of other subtypes. Patients with active NRF2 pathway show resistance to platinum-based therapy and lower overall survival. | [58] |
| PUMA | A2780 and SKOV3 cells | PUMA-overexpressed in A2780 and SKOV3 cells shows increased ROS generation and increased NRF2, HO-1 expression and apoptosis. | [64] |