Upregulation of NR4A3 increases sensitivity to niraparib in ovarian cancer cells resistant to this drug
Acquired resistance is the major clinical change for patients with ovarian cancer undergoing niraparib (NRP) treatment. Targeting NRP-resistant cells would be NRP offers an effective strategy for reversing resistance and inhibiting disease progression. NR4A3 is known as a tumor suppressor in multiple cancers, but its role in NRP resistance of ovarian cancer is still unclear. NRP-resistant ovarian cancer cell lines (A2780/NRP and OVCAR3/NRP) were established by gradually increasing NRP concentrations. The phenotype of resistant cell lines was characterized using proliferation, colony formation, and migration assays. RNA sequencing was performed to identify genes dysregulated in the resistant cell lines. We also performed gain- and loss-of-function assays to investigate the role of NR4A3 in NRP resistance. The resistance indices for A2780/NRP and OVCAR3/NRP were 8.95 and 4.42, respectively. These resistant cells exhibited slower proliferation and robust colony formation and migration abilities. NR4A3 exhibited the highest average log2 fold change among the candidates. Overexpression of NR4A3 sensitized the NRP-resistant cells and reduced their proliferation, colony formation, and migration capabilities, whereas downregulation of NR4A3 in the parental cells caused opposite results. Downregulation of NR4A3 contributes to NRP resistance, and activation of NR4A3 maybe a promising strategy to reverse NRP resistance.