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

¹ Institute of Biosciences and Technology, Texas A&M University Health Science Center; ² Division of Pathology and Laboratory Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas; and Departments of ³ Veterinary Physiology and Pharmacology and ⁴ Pathobiology, Texas A&M University, College Station, Texas

Requests for reprints: Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, Veterinary Research Building 410, College Station, TX 77843-4466. Phone: 979-845-5988; Fax: 979-862-4929; E-mail: ssafe{at}cvm.tamu.edu.

Nerve growth factor–induced B (NGFI-B, 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-pPhOCH₃) 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-pPhOCH₃ 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-pPhOCH₃ was significantly inhibited by a small inhibitory RNA for Nur77 (iNur77); however, it was evident from RNA interference studies that DIM-C-pPhOCH₃ also induced Nur77-independent apoptosis. Analysis of DIM-C-pPhOCH₃–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-pPhOCH₃ (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 receptor-dependent and receptor-independent pathways. [Cancer Res 2007;67(2):674–83]

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