metribolone

Summary

Summary: A synthetic non-aromatizable androgen and anabolic steroid. It binds strongly to the androgen receptor and has therefore also been used as an affinity label for this receptor in the prostate and in prostatic tumors.

Top Publications

  1. Hendriksen P, Dits N, Kokame K, Veldhoven A, Van Weerden W, Bangma C, et al. Evolution of the androgen receptor pathway during progression of prostate cancer. Cancer Res. 2006;66:5012-20 pubmed
    ..The progression from low-grade to high-grade prostate carcinoma and metastases is mediated by a selective down-regulation of the androgen receptor target genes that inhibit proliferation, induce differentiation, or mediate apoptosis. ..
  2. Kokontis J, Hay N, Liao S. Progression of LNCaP prostate tumor cells during androgen deprivation: hormone-independent growth, repression of proliferation by androgen, and role for p27Kip1 in androgen-induced cell cycle arrest. Mol Endocrinol. 1998;12:941-53 pubmed
    ..From these results we conclude that androgenic repression of LNCaP 104-R1 and 104-R2 cell proliferation is due to the induction of p27Kip1, which in turn inhibits Cdk2, a factor critical for cell cycle progression and proliferation. ..
  3. Wegiel B, Bjartell A, Ekberg J, Gadaleanu V, Brunhoff C, Persson J. A role for cyclin A1 in mediating the autocrine expression of vascular endothelial growth factor in prostate cancer. Oncogene. 2005;24:6385-93 pubmed
    ..This suggests that cyclin A1 mediates VEGF expression in cooperation with Rb- and androgen-dependent pathways in prostate cancer. ..
  4. Hanson J, Gorman J, Reese J, Fraizer G. Regulation of vascular endothelial growth factor, VEGF, gene promoter by the tumor suppressor, WT1. Front Biosci. 2007;12:2279-90 pubmed
    ..These findings may shed light on the role of WT1 in angiogenesis and prostate cancer progression. ..
  5. Ngan S, Stronach E, Photiou A, Waxman J, Ali S, Buluwela L. Microarray coupled to quantitative RT-PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells. Oncogene. 2009;28:2051-63 pubmed publisher
  6. Makkonen H, Kauhanen M, Jääskeläinen T, Palvimo J. Androgen receptor amplification is reflected in the transcriptional responses of Vertebral-Cancer of the Prostate cells. Mol Cell Endocrinol. 2011;331:57-65 pubmed publisher
    ..These results support the notion that the AR protein level translates into augmented occupancy of AR-regulated enhancers and target gene activity in prostate cancer cells. ..
  7. Pinthus J, Bryskin I, Trachtenberg J, Lu J, Singh G, Fridman E, et al. Androgen induces adaptation to oxidative stress in prostate cancer: implications for treatment with radiation therapy. Neoplasia. 2007;9:68-80 pubmed
    ..Thus, testosterone induces a preset cellular adaptation to radiation through the generation of elevated bROS, which is modified by AD. These findings provide a rational for combined hormonal and radiation therapy for localized PC. ..
  8. DePrimo S, Diehn M, Nelson J, Reiter R, Matese J, Fero M, et al. Transcriptional programs activated by exposure of human prostate cancer cells to androgen. Genome Biol. 2002;3:RESEARCH0032 pubmed
    ..These results provide a broad view of the effect of androgen signaling on the transcriptional program in these cancer cells, and a foundation for further studies of androgen action. ..
  9. Ortel B, Sharlin D, O Donnell D, Sinha A, Maytin E, Hasan T. Differentiation enhances aminolevulinic acid-dependent photodynamic treatment of LNCaP prostate cancer cells. Br J Cancer. 2002;87:1321-7 pubmed
    ..This study suggests that it will be feasible to develop protocols combining short-term differentiation therapy with photodynamic therapy for enhanced photosensitisation. ..

More Information

Publications62

  1. Lu S, Jenster G, Epner D. Androgen induction of cyclin-dependent kinase inhibitor p21 gene: role of androgen receptor and transcription factor Sp1 complex. Mol Endocrinol. 2000;14:753-60 pubmed
  2. Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, et al. Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. EMBO J. 2000;19:5406-17 pubmed
    ..The role of this phosphotyrosine is stressed by its requirement for association of oestradiol receptor alpha with Src and consequent activation of Src in intact Cos cells. ..
  3. Kimura K, Markowski M, Bowen C, Gelmann E. Androgen blocks apoptosis of hormone-dependent prostate cancer cells. Cancer Res. 2001;61:5611-8 pubmed
    ..The data suggest that androgen induced blockade of caspase activation in both intrinsic and extrinsic cell death pathways and thereby was able to protect prostate cancer cells from apoptosis induced by diverse stimuli. ..
  4. Makkonen H, Kauhanen M, Paakinaho V, Jääskeläinen T, Palvimo J. Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers. Nucleic Acids Res. 2009;37:4135-48 pubmed publisher
    ..Our results indicate that very distal AREs act as genuine and robust enhancers, highlighting the importance of long-range regulation of transcription by the AR. ..
  5. Blankvoort B, de Groene E, van Meeteren Kreikamp A, Witkamp R, Rodenburg R, Aarts J. Development of an androgen reporter gene assay (AR-LUX) utilizing a human cell line with an endogenously regulated androgen receptor. Anal Biochem. 2001;298:93-102 pubmed
    ..The 96-well plate format makes the assay particularly suitable for high-throughput screening. ..
  6. Fiorelli A, Ricciardi C, Pannone G, Santoro A, Bufo P, Santini M, et al. Interplay between steroid receptors and neoplastic progression in sarcoma tumors. J Cell Physiol. 2011;226:2997-3003 pubmed publisher
    ..These findings suggest that there is a crosstalk among AR, ER, and EGFR that lead to src activation also in fibrosarcoma cells. ..
  7. Shi Y, Yu Y, Zhu Z, Han Y, Ren B, Nelson J, et al. MCM7 interacts with androgen receptor. Am J Pathol. 2008;173:1758-67 pubmed publisher
    ..Thus, this study reveals a novel mechanism by which AR and MCM7 facilitate each other's function, suggesting that AR-independent activation of MCM7 may be a mechanism by which prostate cancers bypass therapeutically induced AR blockade. ..
  8. Chipuk J, Cornelius S, Pultz N, Jorgensen J, Bonham M, Kim S, et al. The androgen receptor represses transforming growth factor-beta signaling through interaction with Smad3. J Biol Chem. 2002;277:1240-8 pubmed
    ..In conclusion, our data demonstrate for the first time that ligand-bound AR inhibits TGF-beta transcriptional responses through selectively repressing the binding of Smad3 to SBE. ..
  9. Agoulnik I, Vaid A, Nakka M, Alvarado M, Bingman W, Erdem H, et al. Androgens modulate expression of transcription intermediary factor 2, an androgen receptor coactivator whose expression level correlates with early biochemical recurrence in prostate cancer. Cancer Res. 2006;66:10594-602 pubmed
    ..The elevated expression of TIF2 at low hormone levels likely aids in inducing AR activity under these conditions; treatment with Casodex has the potential to counteract this induction. ..
  10. Sinha A, Anand S, Ortel B, Chang Y, Mai Z, Hasan T, et al. Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells. Br J Cancer. 2006;95:485-95 pubmed
    ..Our data suggest that MTX, when used to modulate intracellular production of endogenous PpIX, may provide a new combination PDT approach for certain cancers. ..
  11. Schatten H, Ripple M, Balczon R, Weindruch R, Chakrabarti A, Taylor M, et al. Androgen and taxol cause cell type-specific alterations of centrosome and DNA organization in androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cells. J Cell Biochem. 2000;76:463-77 pubmed
    ..These results suggest that LNCaP and DU145 prostate cancer cells show differences not only in androgen responsiveness but in sensitivity to taxol as well. ..
  12. Zhang Y, Gong M, Yuan H, Park H, Frierson H, Li H. Chimeric transcript generated by cis-splicing of adjacent genes regulates prostate cancer cell proliferation. Cancer Discov. 2012;2:598-607 pubmed publisher
    ..SLC45A3-ELK4 controls prostate cancer cell proliferation, and the chimera level correlates with prostate cancer disease progression. ..
  13. Sunahara G, Pak R, Bellward G. Effect of flutamide on hepatic cytosolic methyltrienolone (R1881) binding kinetics and testosterone responsive hepatic drug and steroid metabolism in the adult male rat. Biochem Pharmacol. 1987;36:3571-7 pubmed
  14. Rickman D, Pflueger D, Moss B, VanDoren V, Chen C, De La Taille A, et al. SLC45A3-ELK4 is a novel and frequent erythroblast transformation-specific fusion transcript in prostate cancer. Cancer Res. 2009;69:2734-8 pubmed publisher
    ..g., trans-splicing). ..
  15. Whitaker H, Stanbury D, Brinham C, Girling J, Hanrahan S, Totty N, et al. Labeling and identification of LNCaP cell surface proteins: a pilot study. Prostate. 2007;67:943-54 pubmed
    ..We have demonstrated the identification of androgen-regulated membrane proteins and their validation in tissue samples. ..
  16. Ni L, Llewellyn R, Kesler C, Kelley J, Spencer A, Snow C, et al. Androgen induces a switch from cytoplasmic retention to nuclear import of the androgen receptor. Mol Cell Biol. 2013;33:4766-78 pubmed publisher
    ..Importin 7 contributes to the regulation of AR import by restraining import until androgen is detected in the cytoplasm. ..
  17. Gavrielides M, Gonzalez Guerrico A, Riobo N, Kazanietz M. Androgens regulate protein kinase Cdelta transcription and modulate its apoptotic function in prostate cancer cells. Cancer Res. 2006;66:11792-801 pubmed
    ..Our studies identified a novel hormonal mechanism for the control of PKCdelta expression via transcriptional regulation that fine-tunes the magnitude of PKCdelta apoptotic responses. ..
  18. Takeda A, Pinon G, Bens M, Fagart J, Rafestin Oblin M, Vandewalle A. The synthetic androgen methyltrienolone (r1881) acts as a potent antagonist of the mineralocorticoid receptor. Mol Pharmacol. 2007;71:473-82 pubmed
  19. Castoria G, D Amato L, Ciociola A, Giovannelli P, Giraldi T, Sepe L, et al. Androgen-induced cell migration: role of androgen receptor/filamin A association. PLoS ONE. 2011;6:e17218 pubmed publisher
    ..Assembly of this ternary complex may control organ development and prostate cancer metastasis. ..
  20. Otsuka T, Iguchi K, Fukami K, Ishii K, Usui S, Sugimura Y, et al. Androgen receptor W741C and T877A mutations in AIDL cells, an androgen-independent subline of prostate cancer LNCaP cells. Tumour Biol. 2011;32:1097-102 pubmed publisher
    ..Double T877A and W741C AR mutants have been previously reported to exhibit reduced androgen sensitivity. Hence, the low-androgen-sensitive responses of AIDL cells may be explained, at least in part, by AR gene mutations. ..
  21. Xu L, Su Y, LaBiche R, Segawa T, Shanmugam N, McLeod D, et al. Quantitative expression profile of androgen-regulated genes in prostate cancer cells and identification of prostate-specific genes. Int J Cancer. 2001;92:322-8 pubmed
    ..The discovery of new prostate-specific genes and ARGs provides a unique opportunity to determine the role of these genes in prostate cell growth, differentiation and tumorigenesis. ..
  22. Qi H, Labrie Y, Grenier J, Fournier A, Fillion C, Labrie C. Androgens induce expression of SPAK, a STE20/SPS1-related kinase, in LNCaP human prostate cancer cells. Mol Cell Endocrinol. 2001;182:181-92 pubmed
    ..These results identify SPAK, a member of a key cell signalling pathway, as an androgen-responsive gene in LNCaP cells. We hypothesize that SPAK may mediate androgen action in the normal and cancerous prostate gland. ..
  23. Teng C, Goodwin B, Shockley K, Xia M, Huang R, Norris J, et al. Bisphenol A affects androgen receptor function via multiple mechanisms. Chem Biol Interact. 2013;203:556-64 pubmed publisher
    ..Although BPA was able to bind AR, the nuclear translocation was reduced. Furthermore, BPA was unable to induce functional foci in the nuclei and is consistent with the transient transfection study that BPA is unable to activate AR. ..
  24. Morvillo V, Luthy I, Bravo A, Capurro M, Donaldson M, Quintans C, et al. Atypical androgen receptor in the human melanoma cell line IIB-MEL-J. Pigment Cell Res. 1995;8:135-41 pubmed
  25. James A, Agoulnik I, Harris J, Buchanan G, Tilley W, Marcelli M, et al. A novel androgen receptor mutant, A748T, exhibits hormone concentration-dependent defects in nuclear accumulation and activity despite normal hormone-binding affinity. Mol Endocrinol. 2002;16:2692-705 pubmed
    ..Consistent with this conclusion, our structural model predicts that A748T disrupts crucial contact points with ligand, thereby altering the conformation of the ligand-binding domain. ..
  26. Moon J, Lee M, Park S, Han W, Hong S, Ahn J, et al. Androgen-dependent activation of human cytomegalovirus major immediate-early promoter in prostate cancer cells. Prostate. 2008;68:1450-60 pubmed publisher
    ..These results support the possibility that activation of the HCMV MIE promoter by androgen in the prostate could cause the productive infection, which might contribute to oncomodulation in prostate cancers. ..
  27. Risek B, Bilski P, Rice A, Schrader W. Androgen receptor-mediated apoptosis is regulated by photoactivatable androgen receptor ligands. Mol Endocrinol. 2008;22:2099-115 pubmed publisher
    ..Other photoactivatable ligands are described, implying a general method for ablation of cells bearing specific nuclear hormone receptors. ..
  28. Lee S, Lou W, Hou M, Onate S, Gao A. Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway. Oncogene. 2003;22:7981-8 pubmed
    ..Understanding IL-4-induced signaling leading to abnormal activation of AR will provide insights into the molecular mechanisms of androgen-independent progression of prostate cancer cells. ..
  29. Miller G, Stapleton G, Ferrara J, Lucia M, Pfister S, Hedlund T, et al. The human prostatic carcinoma cell line LNCaP expresses biologically active, specific receptors for 1 alpha,25-dihydroxyvitamin D3. Cancer Res. 1992;52:515-20 pubmed
    ..These studies suggest that 1 alpha,25(OH)2D3 could play an important role in the natural history of and response to hormone therapy by prostatic cancer. ..
  30. Thompson V, Morris T, Cochrane D, Cavanagh J, Wafa L, Hamilton T, et al. Relaxin becomes upregulated during prostate cancer progression to androgen independence and is negatively regulated by androgens. Prostate. 2006;66:1698-709 pubmed
    ..The role of relaxin in angiogenesis and tissue remodeling suggests it may contribute to prostate cancer progression. ..
  31. Agoulnik I, Krause W, Bingman W, Rahman H, Amrikachi M, Ayala G, et al. Repressors of androgen and progesterone receptor action. J Biol Chem. 2003;278:31136-48 pubmed
    ..We found that although DAX-1 is expressed in normal human prostate, its expression is strongly reduced in benign prostatic hyperplasia suggesting that DAX-1 plays a role in limiting AR activity in prostate. ..
  32. Ye D, Mendelsohn J, Fan Z. Androgen and epidermal growth factor down-regulate cyclin-dependent kinase inhibitor p27Kip1 and costimulate proliferation of MDA PCa 2a and MDA PCa 2b prostate cancer cells. Clin Cancer Res. 1999;5:2171-7 pubmed
    ..Our results demonstrate the importance of counteracting both androgen receptors and EGF receptors in the development of novel therapies for prostate cancer. ..
  33. Tripepi S, Carelli A, Perrotta E, Brunelli E, Tavolaro R, Facciolo R, et al. Morphological and functional variations of Leydig cells in testis of the domestic pig during the different biological stages of development. J Exp Zool. 2000;287:167-75 pubmed
  34. Li Y, Zheng Y, Izumi K, Ishiguro H, Ye B, Li F, et al. Androgen activates ?-catenin signaling in bladder cancer cells. Endocr Relat Cancer. 2013;20:293-304 pubmed publisher
  35. Varisli L, Gonen Korkmaz C, Syed H, Bogurcu N, Debelec Butuner B, Erbaykent Tepedelen B, et al. Androgen regulated HN1 leads proteosomal degradation of androgen receptor (AR) and negatively influences AR mediated transactivation in prostate cells. Mol Cell Endocrinol. 2012;350:107-17 pubmed publisher
    ..This work has important implications for prostate cancer research, as AR, EGFR and HN1 are known to be highly expressed in prostate adenocarcinomas. ..
  36. Brayman M, Pepa P, Berdy S, Mellon P. Androgen receptor repression of GnRH gene transcription. Mol Endocrinol. 2012;26:2-13 pubmed publisher
  37. Fiebitz A, Vanhecke D. High-throughput mammalian two-hybrid screening for protein-protein interactions using transfected cell arrays (CAPPIA). Methods Mol Biol. 2011;723:165-83 pubmed publisher
  38. Bonagura T, Deng M, Brown T. A naturally occurring mutation in the human androgen receptor of a subject with complete androgen insensitivity confers binding and transactivation by estradiol. Mol Cell Endocrinol. 2007;263:79-89 pubmed
  39. Husbeck B, Bhattacharyya R, Feldman D, Knox S. Inhibition of androgen receptor signaling by selenite and methylseleninic acid in prostate cancer cells: two distinct mechanisms of action. Mol Cancer Ther. 2006;5:2078-85 pubmed
    ..In conclusion, we have found that selenite and MSeA disrupt AR signaling by distinct mechanisms. The inhibition of AR expression and activity by selenite occurs via a redox mechanism involving GSH, superoxide, and Sp1. ..
  40. Hieronymus H, Lamb J, Ross K, Peng X, Clement C, Rodina A, et al. Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006;10:321-30 pubmed
    ..Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy. ..
  41. Brüggenwirth H, Boehmer A, Ramnarain S, Verleun Mooijman M, Satijn D, Trapman J, et al. Molecular analysis of the androgen-receptor gene in a family with receptor-positive partial androgen insensitivity: an unusual type of intronic mutation. Am J Hum Genet. 1997;61:1067-77 pubmed
    ..Translation of the extended transcript resulted in an androgen-receptor protein with 23 amino acid residues inserted between the two zinc clusters, displaying defective DNA binding and defective transcription activation. ..
  42. Huang H, Muddiman D, Tindall D. Androgens negatively regulate forkhead transcription factor FKHR (FOXO1) through a proteolytic mechanism in prostate cancer cells. J Biol Chem. 2004;279:13866-77 pubmed
    ..This provides a mechanism by which androgens protect prostate cancer cells from the killing effect of FKHR. ..
  43. Read J, Rahmani M, Boroomand S, Allahverdian S, McManus B, Rennie P. Androgen receptor regulation of the versican gene through an androgen response element in the proximal promoter. J Biol Chem. 2007;282:31954-63 pubmed
    ..8-fold in fibroblasts. In conclusion, we demonstrate that AR transactivates versican expression, which may augment tumor-stromal interactions and may contribute to prostate cancer progression. ..
  44. Sood A, Saxena R, Groth J, Desouki M, Cheewakriangkrai C, Rodabaugh K, et al. Expression characteristics of prostate-derived Ets factor support a role in breast and prostate cancer progression. Hum Pathol. 2007;38:1628-38 pubmed
    ..Together, these results for the first time show frequent increased expression of PDEF protein in breast and prostate tumors and support a role for PDEF in breast and prostate cancer progression. ..
  45. Gross M, Top I, Laux I, Katz J, Curran J, Tindell C, et al. Beta-2-microglobulin is an androgen-regulated secreted protein elevated in serum of patients with advanced prostate cancer. Clin Cancer Res. 2007;13:1979-86 pubmed
    ..Additional studies are warranted to explore if B2M is as useful marker for prostate cancer. Identification of proteins secreted from cancer cells in preclinical models may be a useful strategy for biomarker discovery. ..
  46. Takahashi Y, Hursting S, Perkins S, Wang T, Wang T. Genistein affects androgen-responsive genes through both androgen- and estrogen-induced signaling pathways. Mol Carcinog. 2006;45:18-25 pubmed
    ..These results indicate that genistein selectively alters expression of ARG mRNAs in LNCaP cells through modulation of both androgen- and estrogen-induced signaling pathways. ..
  47. Mulholland D, Cheng H, Reid K, Rennie P, Nelson C. The androgen receptor can promote beta-catenin nuclear translocation independently of adenomatous polyposis coli. J Biol Chem. 2002;277:17933-43 pubmed
    ..AR-mediated import represents a novel mode of nuclear accumulation of beta-catenin. ..
  48. Singh J, Young L, Handelsman D, Dong Q. Molecular cloning and characterization of a novel androgen repressible gene expressed in the prostate epithelium. Gene. 2005;348:55-63 pubmed
    ..Cloning and characterization of ADMP has made it feasible to determine its prospective role in the absence of androgens in prostate cancer. ..
  49. Yin L, Rao P, Elson P, Wang J, Ittmann M, Heston W. Role of TMPRSS2-ERG gene fusion in negative regulation of PSMA expression. PLoS ONE. 2011;6:e21319 pubmed publisher
    ..Our data indicated that downregulation of PSMA in androgen-treated VCaP cells appears partially mediated by TMPRSS2-ERG gene fusion. ..
  50. Jiang J, Wang L, Fang Y, Jin F, Jin W. Proliferative response of human prostate cancer cell to hormone inhibited by androgen receptor antisense RNA. Chin Med J (Engl). 2004;117:684-8 pubmed
  51. Freyberger A, Ahr H. Development and standardization of a simple binding assay for the detection of compounds with affinity for the androgen receptor. Toxicology. 2004;195:113-26 pubmed
    ..The assay is simple and sensitive, avoids the use of animals as a receptor source, and should be of value when screening for endocrine-modulating compounds. ..
  52. Péant B, Diallo J, Lessard L, Delvoye N, Le Page C, Saad F, et al. Regulation of IkappaB kinase epsilon expression by the androgen receptor and the nuclear factor-kappaB transcription factor in prostate cancer. Mol Cancer Res. 2007;5:87-94 pubmed
    ..To our knowledge, this is the first report of an IkappaB kinase family member whose expression is modulated by androgen and deregulated in androgen receptor-negative cells. ..
  53. Fimmel S, Saborowski A, Terouanne B, Sultan C, Zouboulis C. Inhibition of the androgen receptor by antisense oligonucleotides regulates the biological activity of androgens in SZ95 sebocytes. Horm Metab Res. 2007;39:149-56 pubmed