Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

Abstract

Nuclear receptors are of integral importance in carcinogenesis. Manipulation of classic ligand-activated nuclear receptors, such as estrogen receptor blockade in breast cancer, is an important established cancer therapy. Orphan nuclear receptors, such as nuclear family 4 subgroup A (NR4A) receptors, have no known natural ligand(s). These elusive receptors are increasingly recognized as molecular switches in cell survival and a molecular link between inflammation and cancer. NR4A receptors act as transcription factors, altering expression of downstream genes in apoptosis (Fas-ligand, TRAIL), proliferation, DNA repair, metabolism, cell migration, inflammation (interleukin-8), and angiogenesis (VEGF). NR4A receptors are modulated by multiple cell-signaling pathways, including protein kinase A/CREB, NF-kB, phosphoinositide 3-kinase/AKT, c-jun-NH 2 -kinase, Wnt, and mitogen-activated protein kinase pathways. NR4A receptor effects are context and tissue specific, influenced by their levels of expression, posttranslational modification, and interaction with other transcription factors (RXR, PPAR-¡). The subcellular location of NR4A "nuclear receptors" is also important functionally; novel roles have been described in the cytoplasm where NR4A proteins act both indirectly and directly on the mitochondria to promote apoptosis via Bcl-2. NR4A receptors are implicated in a wide variety of malignancies, including breast, lung, colon, bladder, and prostate cancer; glioblastoma multiforme; sarcoma; and acute and/or chronic myeloid leukemia. NR4A receptors modulate response to conventional chemotherapy and represent an exciting frontier for chemotherapeutic intervention, as novel agents targeting NR4A receptors have now been developed. This review provides a concise clinical overview of current knowledge of NR4A signaling in cancer and the potential for therapeutic manipulation.

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

“…No natural ligand for NR4A1 has yet been identified (Davis and Lau, 1994;Mohan et al, 2012). NR4A1 is thought to play a role in transcriptional regulation through binding of the ZnF_C4 domain to hormone response elements in DNA (Moehren et al, 2004).…”

“…NR4A1 is involved in multiple molecular processes, including signal transmission, transcriptional regulation, mediation of cell growth, induction of apoptosis, and cell cycle control (Lee et al, 2011;McMorrow and Murphy, 2011;Mohan et al, 2012;van Tiel and de Vries, 2012). NR4A1 acts as a hormone receptor and is stimulated by ligand binding to move into the nucleus and associate with DNA to regulate transcription of multiple genes (Wu et al, 2002).…”

“…NR4A1 acts as an inflammatory factor in T-cell, and T-cell receptor-mediated apoptosis can be prevented by inhibiting NR4A1 function (Liu et al, 1994;Woronicz et al, 1994). Thus, it appears that NR4A1 plays different and opposing roles in cell survival and apoptosis depending on the cell status and molecular environment (Mohan et al, 2012). Neuronal regulation GFP-tagged NR4A1 is associated with dopamine receptor D1 positive neurons in brain tissue of transgenic mice (Davis and Puhl, 2011).…”

“…Note It is well known that tumor growth depends on new blood vessel formation to facilitate nutrient delivery (Liu et al, 2003;Mohan et al, 2012). NR4A1 expression is enhanced by vascular endothelial growth factor (Arkenbout et al, 2003;Liu et al, 2003).…”

“…In addition, NR4A1 is activated by overexpression of hypoxia-inducible factor-1 alpha and thereby promotes overproduction of the hormone precursor proopiomelanocortin in VHL-mutated renal cell carcinoma (Choi et al, 2004). 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).…”