Abstract
Early studies suggested both TR3 orphan receptor (TR3) and apoptosis mediator E2F1 might play an important role in mediating prostate cancer cell apoptosis. Their linkage and relationship, however, remain unclear. Here we found that 12-O-tetradecanoylphorbol-13-acetate (TPA) could induce cell apoptosis via induction of TR3 and E2F1 expression in LNCaP prostate cancer cells. Addition of antisense E2F1 could partially rescue the TR3-mediated cell apoptosis, and transfection of the TR3 dominant-negative plasmid could block the TR3-induced E2F1 expression. These data suggest that TPA is able to induce LNCaP cell apoptosis via induction of TR3 resulting in the induction of E2F1. Promoter reporter assays show that TR3 can induce E2F1 expression via binding to the TR3 response element (TR3RE) in the E2F1 promoter -316 to -324 bp region. TR3 can bind specifically to this TR3RE with a Kd of 6.29 nm, and mutations of this E2F1-TR3RE can partially block the TR3-mediated E2F1 expression. Taken together, these data suggest that TPA is able to induce cell apoptosis via a TPA --> TR3 --> E2F1 --> apoptosis pathway in LNCaP cells. Further studies of how to modulate this pathway may allow us to better understand how to control the prostate cancer growth.
Highlights
Human TR3 orphan receptor, isolated by our laboratory [1], is the human homologue of mouse Nur-77 [2] and rat NGFIB [3, 4] genes
We studied the effect of TPA on these two prostate cancer cell lines and studied molecules that mediate the TPA effect
These contrasting effects of TPA raised our interest to further examine cell deathrelated gene expression in these two cell lines. We found that both TR3 and transcription factor E2F1 were greatly induced in LNCaP cells but not in PC-3 cells (Fig. 1B)
Summary
Human TR3 orphan receptor, isolated by our laboratory [1], is the human homologue of mouse Nur-77 [2] and rat NGFIB [3, 4] genes. TR3 was shown to form heterodimers with retinoid X receptor and to confer 9-cis-retinoic acid-dependent transcription to a reporter containing direct repeat (DR) 5 regulator element and TR3RE sequence [16]. Androgen deprivation has been a standard means of hormonal therapy for advanced prostate cancer patients, the molecular mechanism of androgen deprivation-induced prostatic apoptosis remains largely unknown. Both TR3 and E2F1 mediate cancer cell apoptosis [5,6,7,8,9,10,11]; the linkage between them is unclear. We report that TR3 regulates the apoptosis by directly binding and up-regulating E2F1 in human prostate cancer LNCaP cells
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