Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1992 Mar;65(3):376–382. doi: 10.1038/bjc.1992.76

Transcriptional down-regulation of c-myc in human prostate carcinoma cells by the synthetic androgen mibolerone.

D A Wolf 1, F Kohlhuber 1, P Schulz 1, F Fittler 1, D Eick 1
PMCID: PMC1977595  PMID: 1373070

Abstract

The mechanism of down-regulation of c-myc RNA associated with androgen-induced suppression of the transformed phenotype in the human prostate carcinoma cell line LNCaP was investigated. The synthetic androgen mibolerone (7 alpha-17 alpha-Dimethyl-19-nortestosterone) reversibly inhibits the proliferation of LNCaP cells and, from 12-72 h after hormone addition reduces the level of c-myc transcripts to a few per cent of controls. P1, P2, and P0 c-myc transcripts decline at the same rate, whereas P3 transcripts are much less hormone sensitive. Nuclear run-on analysis revealed that c-myc is down-regulated at the level of transcription initiation in LNCaP cells. The level of c-myc transcripts prevailing in untreated control cells can be restored in androgen-induced cells by excess antiandrogen, indicating the involvement of the androgen receptor in c-myc down-regulation.

Full text

PDF
380

Images in this article

378Figure 2
on p.378
379Figure 3
on p.379
380Figure 4
on p.380

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen R. W., Trach K. A., Hoch J. A. Identification of the 37-kDa protein displaying a variable interaction with the erythroid cell membrane as glyceraldehyde-3-phosphate dehydrogenase. J Biol Chem. 1987 Jan 15;262(2):649–653. [PubMed] [Google Scholar]
  2. Asselin C., Nepveu A., Marcu K. B. Molecular requirements for transcriptional initiation of the murine c-myc gene. Oncogene. 1989 May;4(5):549–558. [PubMed] [Google Scholar]
  3. Battey J., Moulding C., Taub R., Murphy W., Stewart T., Potter H., Lenoir G., Leder P. The human c-myc oncogene: structural consequences of translocation into the IgH locus in Burkitt lymphoma. Cell. 1983 Oct;34(3):779–787. doi: 10.1016/0092-8674(83)90534-2. [DOI] [PubMed] [Google Scholar]
  4. Beato M. Gene regulation by steroid hormones. Cell. 1989 Feb 10;56(3):335–344. doi: 10.1016/0092-8674(89)90237-7. [DOI] [PubMed] [Google Scholar]
  5. Bentley D. L., Groudine M. A block to elongation is largely responsible for decreased transcription of c-myc in differentiated HL60 cells. Nature. 1986 Jun 12;321(6071):702–706. doi: 10.1038/321702a0. [DOI] [PubMed] [Google Scholar]
  6. Bentley D. L., Groudine M. Novel promoter upstream of the human c-myc gene and regulation of c-myc expression in B-cell lymphomas. Mol Cell Biol. 1986 Oct;6(10):3481–3489. doi: 10.1128/mcb.6.10.3481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bentley D. L., Groudine M. Sequence requirements for premature termination of transcription in the human c-myc gene. Cell. 1988 Apr 22;53(2):245–256. doi: 10.1016/0092-8674(88)90386-8. [DOI] [PubMed] [Google Scholar]
  8. Berk A. J., Sharp P. A. Sizing and mapping of early adenovirus mRNAs by gel electrophoresis of S1 endonuclease-digested hybrids. Cell. 1977 Nov;12(3):721–732. doi: 10.1016/0092-8674(77)90272-0. [DOI] [PubMed] [Google Scholar]
  9. Berns E. M., de Boer W., Mulder E. Androgen-dependent growth regulation of and release of specific protein(s) by the androgen receptor containing human prostate tumor cell line LNCaP. Prostate. 1986;9(3):247–259. doi: 10.1002/pros.2990090305. [DOI] [PubMed] [Google Scholar]
  10. Campisi J., Gray H. E., Pardee A. B., Dean M., Sonenshein G. E. Cell-cycle control of c-myc but not c-ras expression is lost following chemical transformation. Cell. 1984 Feb;36(2):241–247. doi: 10.1016/0092-8674(84)90217-4. [DOI] [PubMed] [Google Scholar]
  11. Chung J., Sinn E., Reed R. R., Leder P. Trans-acting elements modulate expression of the human c-myc gene in Burkitt lymphoma cells. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7918–7922. doi: 10.1073/pnas.83.20.7918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Claessens F., Celis L., Peeters B., Heyns W., Verhoeven G., Rombauts W. Functional characterization of an androgen response element in the first intron of the C3(1) gene of prostatic binding protein. Biochem Biophys Res Commun. 1989 Oct 31;164(2):833–840. doi: 10.1016/0006-291x(89)91534-9. [DOI] [PubMed] [Google Scholar]
  13. Cole M. D. The myc oncogene: its role in transformation and differentiation. Annu Rev Genet. 1986;20:361–384. doi: 10.1146/annurev.ge.20.120186.002045. [DOI] [PubMed] [Google Scholar]
  14. Dani C., Blanchard J. M., Piechaczyk M., El Sabouty S., Marty L., Jeanteur P. Extreme instability of myc mRNA in normal and transformed human cells. Proc Natl Acad Sci U S A. 1984 Nov;81(22):7046–7050. doi: 10.1073/pnas.81.22.7046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Duyao M. P., Buckler A. J., Sonenshein G. E. Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4727–4731. doi: 10.1073/pnas.87.12.4727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Eastman-Reks S. B., Vedeckis W. V. Glucocorticoid inhibition of c-myc, c-myb, and c-Ki-ras expression in a mouse lymphoma cell line. Cancer Res. 1986 May;46(5):2457–2462. [PubMed] [Google Scholar]
  17. Eick D., Bornkamm G. W. Transcriptional arrest within the first exon is a fast control mechanism in c-myc gene expression. Nucleic Acids Res. 1986 Nov 11;14(21):8331–8346. doi: 10.1093/nar/14.21.8331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Eick D. Elongation and maturation of c-myc RNA is inhibited by differentiation inducing agents in HL60 cells. Nucleic Acids Res. 1990 Mar 11;18(5):1199–1205. doi: 10.1093/nar/18.5.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Eick D., Piechaczyk M., Henglein B., Blanchard J. M., Traub B., Kofler E., Wiest S., Lenoir G. M., Bornkamm G. W. Aberrant c-myc RNAs of Burkitt's lymphoma cells have longer half-lives. EMBO J. 1985 Dec 30;4(13B):3717–3725. doi: 10.1002/j.1460-2075.1985.tb04140.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Eick D., Polack A., Kofler E., Lenoir G. M., Rickinson A. B., Bornkamm G. W. Expression of P0- and P3-RNA from the normal and translocated c-myc allele in Burkitt's lymphoma cells. Oncogene. 1990 Sep;5(9):1397–1402. [PubMed] [Google Scholar]
  21. Forsthoefel A. M., Thompson E. A. Glucocorticoid regulation of transcription of the c-myc cellular protooncogene in P1798 cells. Mol Endocrinol. 1987 Dec;1(12):899–907. doi: 10.1210/mend-1-12-899. [DOI] [PubMed] [Google Scholar]
  22. Hay N., Bishop J. M., Levens D. Regulatory elements that modulate expression of human c-myc. Genes Dev. 1987 Sep;1(7):659–671. doi: 10.1101/gad.1.7.659. [DOI] [PubMed] [Google Scholar]
  23. Hay N., Takimoto M., Bishop J. M. A FOS protein is present in a complex that binds a negative regulator of MYC. Genes Dev. 1989 Mar;3(3):293–303. doi: 10.1101/gad.3.3.293. [DOI] [PubMed] [Google Scholar]
  24. Hayday A. C., Gillies S. D., Saito H., Wood C., Wiman K., Hayward W. S., Tonegawa S. Activation of a translocated human c-myc gene by an enhancer in the immunoglobulin heavy-chain locus. 1984 Jan 26-Feb 1Nature. 307(5949):334–340. doi: 10.1038/307334a0. [DOI] [PubMed] [Google Scholar]
  25. Horoszewicz J. S., Leong S. S., Chu T. M., Wajsman Z. L., Friedman M., Papsidero L., Kim U., Chai L. S., Kakati S., Arya S. K. The LNCaP cell line--a new model for studies on human prostatic carcinoma. Prog Clin Biol Res. 1980;37:115–132. [PubMed] [Google Scholar]
  26. Horoszewicz J. S., Leong S. S., Kawinski E., Karr J. P., Rosenthal H., Chu T. M., Mirand E. A., Murphy G. P. LNCaP model of human prostatic carcinoma. Cancer Res. 1983 Apr;43(4):1809–1818. [PubMed] [Google Scholar]
  27. Iguchi-Ariga S. M., Okazaki T., Itani T., Ogata M., Sato Y., Ariga H. An initiation site of DNA replication with transcriptional enhancer activity present upstream of the c-myc gene. EMBO J. 1988 Oct;7(10):3135–3142. doi: 10.1002/j.1460-2075.1988.tb03180.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Imagawa M., Chiu R., Karin M. Transcription factor AP-2 mediates induction by two different signal-transduction pathways: protein kinase C and cAMP. Cell. 1987 Oct 23;51(2):251–260. doi: 10.1016/0092-8674(87)90152-8. [DOI] [PubMed] [Google Scholar]
  29. Jonat C., Rahmsdorf H. J., Park K. K., Cato A. C., Gebel S., Ponta H., Herrlich P. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell. 1990 Sep 21;62(6):1189–1204. doi: 10.1016/0092-8674(90)90395-u. [DOI] [PubMed] [Google Scholar]
  30. Kakkis E., Calame K. A plasmacytoma-specific factor binds the c-myc promoter region. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7031–7035. doi: 10.1073/pnas.84.20.7031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kakkis E., Riggs K. J., Gillespie W., Calame K. A transcriptional repressor of c-myc. Nature. 1989 Jun 29;339(6227):718–721. doi: 10.1038/339718a0. [DOI] [PubMed] [Google Scholar]
  32. Kelly K., Cochran B. H., Stiles C. D., Leder P. Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor. Cell. 1983 Dec;35(3 Pt 2):603–610. doi: 10.1016/0092-8674(83)90092-2. [DOI] [PubMed] [Google Scholar]
  33. Lipp M., Schilling R., Wiest S., Laux G., Bornkamm G. W. Target sequences for cis-acting regulation within the dual promoter of the human c-myc gene. Mol Cell Biol. 1987 Apr;7(4):1393–1400. doi: 10.1128/mcb.7.4.1393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Maroder M., Martinotti S., Vacca A., Screpanti I., Petrangeli E., Frati L., Gulino A. Post-transcriptional control of c-myc proto-oncogene expression by glucocorticoid hormones in human T lymphoblastic leukemic cells. Nucleic Acids Res. 1990 Mar 11;18(5):1153–1157. doi: 10.1093/nar/18.5.1153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Miller H., Asselin C., Dufort D., Yang J. Q., Gupta K., Marcu K. B., Nepveu A. A cis-acting element in the promoter region of the murine c-myc gene is necessary for transcriptional block. Mol Cell Biol. 1989 Dec;9(12):5340–5349. doi: 10.1128/mcb.9.12.5340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pietenpol J. A., Holt J. T., Stein R. W., Moses H. L. Transforming growth factor beta 1 suppression of c-myc gene transcription: role in inhibition of keratinocyte proliferation. Proc Natl Acad Sci U S A. 1990 May;87(10):3758–3762. doi: 10.1073/pnas.87.10.3758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Quarmby V. E., Beckman W. C., Jr, Wilson E. M., French F. S. Androgen regulation of c-myc messenger ribonucleic acid levels in rat ventral prostate. Mol Endocrinol. 1987 Dec;1(12):865–874. doi: 10.1210/mend-1-12-865. [DOI] [PubMed] [Google Scholar]
  38. Reitsma P. H., Rothberg P. G., Astrin S. M., Trial J., Bar-Shavit Z., Hall A., Teitelbaum S. L., Kahn A. J. Regulation of myc gene expression in HL-60 leukaemia cells by a vitamin D metabolite. Nature. 1983 Dec 1;306(5942):492–494. doi: 10.1038/306492a0. [DOI] [PubMed] [Google Scholar]
  39. Remmers E. F., Yang J. Q., Marcu K. B. A negative transcriptional control element located upstream of the murine c-myc gene. EMBO J. 1986 May;5(5):899–904. doi: 10.1002/j.1460-2075.1986.tb04301.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rennie P. S., Bruchovsky N., Buttyan R., Benson M., Cheng H. Gene expression during the early phases of regression of the androgen-dependent Shionogi mouse mammary carcinoma. Cancer Res. 1988 Nov 15;48(22):6309–6312. [PubMed] [Google Scholar]
  41. Rories C., Lau C. K., Fink K., Spelsberg T. C. Rapid inhibition of c-myc gene expression by a glucocorticoid in the avian oviduct. Mol Endocrinol. 1989 Jun;3(6):991–1001. doi: 10.1210/mend-3-6-991. [DOI] [PubMed] [Google Scholar]
  42. Sacca R., Cochran B. H. Identification of a PDGF-responsive element in the murine c-myc gene. Oncogene. 1990 Oct;5(10):1499–1505. [PubMed] [Google Scholar]
  43. Schulz P., Bauer H. W., Fittler F. Steroid hormone regulation of prostatic acid phosphatase expression in cultured human prostatic carcinoma cells. Biol Chem Hoppe Seyler. 1985 Nov;366(11):1033–1039. doi: 10.1515/bchm3.1985.366.2.1033. [DOI] [PubMed] [Google Scholar]
  44. Schulz P., Stucka R., Feldmann H., Combriato G., Klobeck H. G., Fittler F. Sequence of a cDNA clone encompassing the complete mature human prostate specific antigen (PSA) and an unspliced leader sequence. Nucleic Acids Res. 1988 Jul 11;16(13):6226–6226. doi: 10.1093/nar/16.13.6226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Schüle R., Rangarajan P., Kliewer S., Ransone L. J., Bolado J., Yang N., Verma I. M., Evans R. M. Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor. Cell. 1990 Sep 21;62(6):1217–1226. doi: 10.1016/0092-8674(90)90397-w. [DOI] [PubMed] [Google Scholar]
  46. Siebenlist U., Bressler P., Kelly K. Two distinct mechanisms of transcriptional control operate on c-myc during differentiation of HL60 cells. Mol Cell Biol. 1988 Feb;8(2):867–874. doi: 10.1128/mcb.8.2.867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Siebenlist U., Hennighausen L., Battey J., Leder P. Chromatin structure and protein binding in the putative regulatory region of the c-myc gene in Burkitt lymphoma. Cell. 1984 Jun;37(2):381–391. doi: 10.1016/0092-8674(84)90368-4. [DOI] [PubMed] [Google Scholar]
  48. Simpson R. U., Hsu T., Begley D. A., Mitchell B. S., Alizadeh B. N. Transcriptional regulation of the c-myc protooncogene by 1,25-dihydroxyvitamin D3 in HL-60 promyelocytic leukemia cells. J Biol Chem. 1987 Mar 25;262(9):4104–4108. [PubMed] [Google Scholar]
  49. Sonnenschein C., Olea N., Pasanen M. E., Soto A. M. Negative controls of cell proliferation: human prostate cancer cells and androgens. Cancer Res. 1989 Jul 1;49(13):3474–3481. [PubMed] [Google Scholar]
  50. Takimoto M., Quinn J. P., Farina A. R., Staudt L. M., Levens D. fos/jun and octamer-binding protein interact with a common site in a negative element of the human c-myc gene. J Biol Chem. 1989 May 25;264(15):8992–8999. [PubMed] [Google Scholar]
  51. Thalmeier K., Synovzik H., Mertz R., Winnacker E. L., Lipp M. Nuclear factor E2F mediates basic transcription and trans-activation by E1a of the human MYC promoter. Genes Dev. 1989 Apr;3(4):527–536. doi: 10.1101/gad.3.4.527. [DOI] [PubMed] [Google Scholar]
  52. Thompson C. B., Challoner P. B., Neiman P. E., Groudine M. Levels of c-myc oncogene mRNA are invariant throughout the cell cycle. 1985 Mar 28-Apr 3Nature. 314(6009):363–366. doi: 10.1038/314363a0. [DOI] [PubMed] [Google Scholar]
  53. Thompson T. C. Growth factors and oncogenes in prostate cancer. Cancer Cells. 1990 Nov;2(11):345–354. [PubMed] [Google Scholar]
  54. Thompson T. C., Southgate J., Kitchener G., Land H. Multistage carcinogenesis induced by ras and myc oncogenes in a reconstituted organ. Cell. 1989 Mar 24;56(6):917–930. doi: 10.1016/0092-8674(89)90625-9. [DOI] [PubMed] [Google Scholar]
  55. Veldscholte J., Ris-Stalpers C., Kuiper G. G., Jenster G., Berrevoets C., Claassen E., van Rooij H. C., Trapman J., Brinkmann A. O., Mulder E. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun. 1990 Dec 14;173(2):534–540. doi: 10.1016/s0006-291x(05)80067-1. [DOI] [PubMed] [Google Scholar]
  56. Wakeling A. E., Furr B. J., Glen A. T., Hughes L. R. Receptor binding and biological activity of steroidal and nonsteroidal antiandrogens. J Steroid Biochem. 1981 Dec;15:355–359. doi: 10.1016/0022-4731(81)90297-1. [DOI] [PubMed] [Google Scholar]
  57. Weisinger G., Remmers E. F., Hearing P., Marcu K. B. Multiple negative elements upstream of the murine c-myc gene share nuclear factor binding sites with SV40 and polyoma enhancers. Oncogene. 1988 Dec;3(6):635–646. [PubMed] [Google Scholar]
  58. Wolf D. A., Schulz P., Fittler F. Synthetic androgens suppress the transformed phenotype in the human prostate carcinoma cell line LNCaP. Br J Cancer. 1991 Jul;64(1):47–53. doi: 10.1038/bjc.1991.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Yang-Yen H. F., Chambard J. C., Sun Y. L., Smeal T., Schmidt T. J., Drouin J., Karin M. Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction. Cell. 1990 Sep 21;62(6):1205–1215. doi: 10.1016/0092-8674(90)90396-v. [DOI] [PubMed] [Google Scholar]
  60. Yuh Y. S., Thompson E. B. Glucocorticoid effect on oncogene/growth gene expression in human T lymphoblastic leukemic cell line CCRF-CEM. Specific c-myc mRNA suppression by dexamethasone. J Biol Chem. 1989 Jun 25;264(18):10904–10910. [PubMed] [Google Scholar]
  61. ar-Rushdi A., Nishikura K., Erikson J., Watt R., Rovera G., Croce C. M. Differential expression of the translocated and the untranslocated c-myc oncogene in Burkitt lymphoma. Science. 1983 Oct 28;222(4622):390–393. doi: 10.1126/science.6414084. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES