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Abstract
Photoreceptor cell-specific receptor (PNR/NR2E3) is an orphan nuclear receptor that plays a critical role in retinal development and photoreceptor maintenance. The disease-causing mutations in PNR have a pleiotropic effect resulting in varying retinal diseases. Recently, PNR has been implicated in control of cellular functions in cancer cells. PNR was reported to be a novel regulator of ERα expression in breast cancer cells, and high PNR expression correlates with favorable response to tamoxifen treatment. Moreover, PNR was shown to increase p53 stability in HeLa cells, implying that PNR may be a therapeutic target in this and other cancers that retain a wild type p53 gene. To facilitate further understanding of PNR functions in cancer, we characterized compound 11a, a synthetic, putative PNR agonist in several cell-based assays. Interestingly, we showed that 11a failed to activate PNR and its cytotoxicity was independent of PNR expression, excluding PNR as a mediator for 11a cytotoxicity. Systematic analyses of the cytotoxic effects of 11a in NCI-60 cell lines revealed a strong positive correlation of cytotoxicity with p53 status, i.e., p53 wild type cell lines were significantly more sensitive to 11a than p53 mutated or null cell lines. Furthermore, using HCT116 p53+/+ and p53-/- isogenic cell lines we revealed that the mechanism of 11a-induced cytotoxicity occurred through G1/S phase cell cycle arrest rather than apoptosis. In conclusion, we observed a correlation of 11a sensitivity with p53 status but not with PNR expression, suggesting that tumors expressing wild type p53 might be responsive to this compound.
Highlights
Nuclear hormone receptors regulate a variety of essential biological processes including development, differentiation and cell survival [1,2,3]
We systematically evaluated the cytotoxic effects of 11a in NCI-60 cell lines [33] and found that 11a cytotoxicity is independent of Photoreceptor-Specific Nuclear Receptor (PNR) expression but positively correlates with p53 status, with higher sensitivity in p53 wild type cell lines than p53 null/mutant cell lines
We evaluated the dependency of 11a cytotoxicity on PNR expression and further investigated the mechanism of 11a cellular cytotoxicity using various cell-based assays
Summary
Nuclear hormone receptors regulate a variety of essential biological processes including development, differentiation and cell survival [1,2,3]. Their activities and expression levels are tightly controlled, and dysregulation of nuclear receptors (NRs) and their coregulators is involved in metabolic diseases and cancer development [4,5,6]. The expression of PNR is significantly associated with recurrence-free survival and favorable tamoxifen response in ERα-positive, node negative breast cancer patients [29] These studies imply that PNR might be a therapeutic target for retinal diseases, cancers retaining a wild type p53 gene, and ERα-positive breast cancers. Using HCT116 p53+/+ and p53-/- isogenic cell lines, we demonstrated that the cytotoxic effects of 11a largely resulted from p53-induced G1/S phase cell cycle arrest, with minor contribution from apoptosis
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