In metastatic
ovarian cancer, resistance to
platinum chemotherapy is common. Although the
orphan nuclear receptor TR3 (nur77/NR4A1) is implicated in mediating
chemotherapy-induced apoptosis in
cancer cells, its role in
ovarian cancer has not been determined. In an
ovarian cancer tissue microarray, TR3
protein expression was elevated in stage I
tumors, but downregulated in a significant subset of metastatic
tumors. Moreover, TR3 expression was significantly lower in
platinum-resistant
tumors in patients with metastatic disease, and low TR3 staining was associated with poorer overall and progression-free survival. We have identified a direct role for TR3 in
cisplatin-induced apoptosis in
ovarian cancer cells. Nucleus-to-cytoplasm translocation of TR3 was observed in
cisplatin-sensitive (OVCAR8, OVCAR3, and A2780PAR) but not
cisplatin-resistant (NCI/ADR-RES and A2780CP20)
ovarian cancer cells. Immunofluorescent analyses showed clear overlap between TR3 and mitochondrial Hsp60 in
cisplatin-treated cells, which was associated with
cytochrome c release.
Ovarian cancer cells with stable
shRNA- or transient
siRNA-mediated TR3 downregulation displayed substantial reduction in
cisplatin effects on apoptotic markers and cell growth in vitro and in vivo. Mechanistic studies showed that the
cisplatin-induced cytoplasmic TR3 translocation required for apoptosis induction was regulated by JNK activation and inhibition of Akt. Finally,
cisplatin resistance was partially overcome by ectopic TR3 overexpression and by treatment with the JNK activator
anisomycin and Akt pathway inhibitor,
wortmannin. Our results suggest that disruption of TR3 activity, via downregulation or nuclear sequestration, likely contributes to
platinum resistance in
ovarian cancer. Moreover, we have described a treatment strategy aimed at overcoming
platinum resistance by targeting TR3.