Nur77 Agonists Induce Proapoptotic Genes and Responses in Colon Cancer Cells through Nuclear Receptor–Dependent and Nuclear Receptor–Independent Pathways

Abstract

Nerve growth factor-induced BA (NGFI-BA, Nur77) is an orphan nuclear receptor with no known endogenous ligands; however, recent studies on a series of methylene-substituted diindolylmethanes (C-DIM) have identified 1,1-bis(3 ¶-indolyl)-1-(phenyl)methane (DIM-C-Ph) and 1,1-bis(3 ¶-indolyl)-1-(p-anisyl)methane (DIM-C-pPhOCH 3 ) as Nur77 agonists. Nur77 is expressed in several colon cancer cell lines (RKO, SW480, HCT-116, HT-29, and HCT-15), and we also observed by immunostaining that Nur77 was overexpressed in colon tumors compared with normal colon tissue. DIM-C-Ph and DIM-C-pPhOCH 3 decreased survival and induced apoptosis in RKO colon cancer cells, and this was accompanied by induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein. The induction of apoptosis and TRAIL by DIM-C-pPhOCH 3 was significantly inhibited by a small inhibitory RNA for Nur77 (iNur77); however, it was evident from RNA interference studies that DIM-C-pPhOCH 3 also induced Nur77-independent apoptosis. Analysis of DIM-C-pPhOCH 3 -induced gene expression using microarrays identified several proapoptotic genes, and analysis by reverse transcription-PCR in the presence or absence of iNur77 showed that induction of programmed cell death gene 1 was Nur77 dependent, whereas induction of cystathionase and activating transcription factor 3 was Nur77 independent. DIM-C-pPhOCH 3 (25 mg/kg/d) also inhibited tumor growth in athymic nude mice bearing RKO cell xenografts. These results show that Nur77-active C-DIM compounds represent a new class of anti-colon cancer drugs that act through receptordependent and receptor-independent pathways. [Cancer Res 2007;67(2):674-83]

Melanocortin-1 Receptor Signaling Markedly Induces the Expression of the NR4A Nuclear Receptor Subgroup in Melanocytic Cells

“…The induction of genotoxic stress is a key component of the anti-proliferative activity of this class of compound, leading to the suggestion that the NR4A subgroup mediates the cellular response to genotoxic stress via the activation of an NR4A transcriptional response (35). With the emergence of pharmacological agents capable of targeting the NR4A nuclear receptors (36,(53)(54)(55), further understanding of the cytoprotective role of this family may have potential implications in the prevention of melanocytic malignancy.…”

Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer

“…When the cancer cells are treated with the specific stimulator for Nurr77, apoptotic induction is observed without Nur77 subcellular distribution changes. 26 This controversy might be explained by cell type-specific behavior or subcellular signaling molecules that modulate NR4A receptor. We have previously shown that Nurr1 is expressed in a panel of 11 human bladder cancer cell lines, and treatment of bladder cancer cells with Nurr1-active-C-DIM resulted in decreased cell survival and induction of cell death pathways.…”

Ring-substituted analogs of 3,3′-diindolylmethane (DIM) induce apoptosis and necrosis in androgen-dependent and –independent prostate cancer cells

“…The diverse molecular targets through which DIM is assumed to exert its anti-proliferative and pro-apoptotic effects have not been identified and DIM-induced necrosis has not been examined. Moreover, the search for compounds exhibiting higher potency and specificity towards prostate tumours is ongoing, and we have studied a number of methyl-substituted derivatives of DIM in other cancerous tissues [19,[25][26][27][28][29][30]. More recently, we have begun to test halogenated forms of the compound in AD prostate cancer cell models [31].…”