TR3 Orphan Nuclear Receptor Mediates Apoptosis through Up-regulating E2F1 in Human Prostate Cancer LNCaP Cells

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 K d 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 3 TR3 3 E2F1 3 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.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

Nuclear orphan receptor TR3/Nur77 mediates melanoma cell apoptosis

“…40 Involvement of TR3 in chemotherapeutic agent induced apoptosis is common, [41][42][43] such as in ATRA-induced MCF-7 breast cancer cell apoptosis, 24 AHPN/CD437-induced lung and prostate cancer cell apoptosis, 41 and butyrate induced apoptosis in HCT116 colon cancer cells. 33 In contrast to other tumors, we showed that ATRA and cisplatin did not upregulate TR3 expression, but rather partially altered its subcellular distribution, and induced melanoma cell apoptosis.…”

Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis

“…Moreover, when endogenous Pin1 was knocked down via Pin1-siRNA, TR3 can no longer influence cyclin D2 expression (Figure 4d, right). In addition, Pin1 also influenced the association of TR3 with the promoter of E2F1 (Supplementary Figure S4E), another target gene of TR3 (Mu and Chang, 2003), accompanying with the upregulation of E2F1 expression (Figure 4d; Supplementary Figure S4F). Together, these results consistently indicate that the prolyl cis/trans isomerization catalyzed by Pin1 is a prerequisite for TR3 to stimulate the expression of its downstream target genes.…”

NR4A1 (nuclear receptor subfamily 4, group A, member 1)

“…Although the studies cited above indicate that NR4A1 contributes to carcinogenesis, many others report the opposite effect of NR4A1 on tumor growth (Mohan et al, 2012). NR4A1 expression is modified to inhibit tumor formation in many tumor types, including colon, breast, bladder, liver, thyroid, lung, prostate, and renal cell carcinoma (Choi et al, 2004;Mohan et al, 2012;Mu and Chang, 2003). As noted earlier, NR4A1 promotes apoptosis in a human prostate cancer cell line through stimulation of E2F1 expression (Mu and Chang, 2003).…”

“…NR4A1 expression is modified to inhibit tumor formation in many tumor types, including colon, breast, bladder, liver, thyroid, lung, prostate, and renal cell carcinoma (Choi et al, 2004;Mohan et al, 2012;Mu and Chang, 2003). As noted earlier, NR4A1 promotes apoptosis in a human prostate cancer cell line through stimulation of E2F1 expression (Mu and Chang, 2003). Early induction of NR4A1 in a human breast cancer cell line causes A23187-induced cell death via the CREB signaling pathway (Ohkubo et al, 2000).…”

“…Apoptosis Contradictory to its apparent role in cell survival, NR4A1 also activates several genes involved in cell apoptosis as well as translocating directly into mitochondria to enhance the apoptotic signal (Li et al, 2000;Lin et al, 2004;Zhang et al, 1999). For example, NR4A1 induces apoptosis in cultured prostate cancer cells through activation of the transcription factor E2F1 (Mu and Chang, 2003;Wilson et al, 2003). NR4A1 also mediates apoptosis through translocation from the nucleus into mitochondria where it interacted with the apoptosis regulating protein Bcl-2 to release cytochrome c (Lin et al, 2004;Suzuki et al, 2003).…”