Skip to main content

Advertisement

Log in

Estrogen prevents sustained COLO-205 human colon cancer cell growth by inducing apoptosis, decreasing c-myb protein, and decreasing transcription of the anti-apoptotic protein bcl-2

  • Research Article
  • Published:
Tumor Biology

Abstract

The proto-oncogene c-myb is overexpressed in human colon cancer cells. c-myb is known to be affected by estrogen in some breast cancers and leukemias. However, the mechanism of c-myb regulation via estrogen in colon cancer requires further investigation. Human COLO-205 colon cancer cells were cultured and treated with beta-estradiol for 24 h. Apoptosis was quantified using acridine orange/propidium iodide labeling and confirmed with DNA fragmentation gel electrophoresis. Expression of c-myb protein was assessed via SDS-PAGE and immunoblotting and RT-PCR was used to quantify bcl-2 RNA. Protein and RNA expression levels were also assayed after c-myb siRNA treatment for 24 h. We demonstrate an increase in apoptosis after 24 h of β-estradiol treatment of human COLO-205 colon cancer cells. Estrogen treatment also decreases c-myb protein levels as well as expression of its transcriptional target bcl-2. Suppression of c-myb protein also results in increased apoptosis and decreases bcl-2 expression. These results indicate that estrogen has a protective effect from sustained colon cancer cell growth at least partly through suppression of c-myb and bcl-2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Jagani Z, Khosravi-Far R. Cancer stem cells and impaired apoptosis. Adv Exp Med Biol. 2008;615:331–44.

    Article  PubMed  Google Scholar 

  2. Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle. 2005;4:1201–15.

    CAS  PubMed  Google Scholar 

  3. Lechner D, Kallay E, Cross HS. Phytoestrogens and colorectal cancer prevention. Vitam Horm. 2005;70:169–98.

    Article  CAS  PubMed  Google Scholar 

  4. Liu X, Lazenby AJ, Siegal GP. Signal transduction cross-talk during colorectal tumorigenesis. Adv Anat Pathol. 2006;13:270–4.

    Article  PubMed  Google Scholar 

  5. Jakowlew SB. Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev. 2006;25:435–57.

    Article  CAS  PubMed  Google Scholar 

  6. Ramocki NM, Wilkins HR, Magness ST, Simmons JG, Scull BP, Lee GH, et al. Insulin receptor substrate-1 deficiency promotes apoptosis in the putative intestinal crypt stem cell region, limits apcmin/+ tumors, and regulates sox9. Endocrinology. 2008;149:261–7.

    Article  CAS  PubMed  Google Scholar 

  7. Torelli G, Venturelli D, Colo A, Zanni C, Selleri L, Moretti L, et al. Expression of c-myb protooncogene and other cell cycle-related genes in normal and neoplastic human colonic mucosa. Cancer Res. 1987;47:5266–9.

    CAS  PubMed  Google Scholar 

  8. Greco C, Alvino S, Buglioni S, Assisi D, Lapenta R, Grassi A, et al. Activation of c-myc and c-myb proto-oncogenes is associated with decreased apoptosis in tumor colon progression. Anticancer Res. 2001;21:3185–92.

    CAS  PubMed  Google Scholar 

  9. Funato T, Satou J, Kozawa K, Fujimaki S, Miura T, Kaku M. Use of c-myb antisense oligonucleotides to increase the sensitivity of human colon cancer cells to cisplatin. Oncol Rep. 2001;8:807–10.

    CAS  PubMed  Google Scholar 

  10. Frampton J, Ramqvist T, Graf T. V-myb of e26 leukemia virus up-regulates bcl-2 and suppresses apoptosis in myeloid cells. Genes Dev. 1996;10:2720–31.

    Article  CAS  PubMed  Google Scholar 

  11. Taylor D, Badiani P, Weston K. A dominant interfering myb mutant causes apoptosis in t cells. Genes Dev. 1996;10:2732–44.

    Article  CAS  PubMed  Google Scholar 

  12. Gupta S, Kass GE, Szegezdi E, Joseph B The mitochondrial death pathway: A promising therapeutic target in diseases. J Cell Mol Med. 2009 (in press)

  13. Kim R, Emi M, Tanabe K. Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol. 2006;57:545–53.

    Article  CAS  PubMed  Google Scholar 

  14. Gonda TJ, Leo P, Ramsay RG. Estrogen and myb in breast cancer: potential for new therapies. Expert Opin Biol Ther. 2008;8:713–17.

    Article  CAS  PubMed  Google Scholar 

  15. Drabsch Y, Hugo H, Zhang R, Dowhan DH, Miao YR, Gewirtz AM, et al. Mechanism of and requirement for estrogen-regulated myb expression in estrogen receptor-positive breast cancer cells. Proc Natl Acad Sci U S A. 2007;104:13762–7.

    Article  CAS  PubMed  Google Scholar 

  16. Gudas JM, Klein RC, Oka M, Cowan KH. Posttranscriptional regulation of the c-myb proto-oncogene in estrogen receptor-positive breast cancer cells. Clin Cancer Res. 1995;1:235–43.

    CAS  PubMed  Google Scholar 

  17. Humphries KH, Gill S. Risks and benefits of hormone replacement therapy: the evidence speaks. Cmaj. 2003;168:1001–10.

    PubMed  Google Scholar 

  18. Lemay A. The relevance of the women's health initiative results on combined hormone replacement therapy in clinical practice. J Obstet Gynaecol Can. 2002;24:711–15.

    PubMed  Google Scholar 

  19. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med. 1999;106:574–82.

    Article  CAS  PubMed  Google Scholar 

  20. Hsu HH, Cheng SF, Wu CC, Chu CH, Weng YJ, Lin CS, et al. Apoptotic effects of over-expressed estrogen receptor-beta on lovo colon cancer cell is mediated by p53 signalings in a ligand-dependent manner. Chin J Physiol. 2006;49:110–16.

    CAS  PubMed  Google Scholar 

  21. Qiu Y, Langman MJ, Eggo MC. Targets of 17beta-oestradiol-induced apoptosis in colon cancer cells: a mechanism for the protective effects of hormone replacement therapy? J Endocrinol. 2004;181:327–37.

    Article  CAS  PubMed  Google Scholar 

  22. Qiu Y, Waters CE, Lewis AE, Langman MJ, Eggo MC. Oestrogen-induced apoptosis in colonocytes expressing oestrogen receptor beta. J Endocrinol. 2002;174:369–77.

    Article  CAS  PubMed  Google Scholar 

  23. Motylewska E, Lawnicka H, Melen-Mucha G. Oestradiol and tamoxifen inhibit murine colon 38 cancer growth and increase the cytotoxic effect of fluorouracil. Endokrynol Pol. 2007;58:426–34.

    PubMed  Google Scholar 

  24. Thompson MA, Rosenthal MA, Ellis SL, Friend AJ, Zorbas MI, Whitehead RH, et al. C-myb down-regulation is associated with human colon cell differentiation, apoptosis, and decreased bcl-2 expression. Cancer Res. 1998;58:5168–75.

    CAS  PubMed  Google Scholar 

  25. Wolff L, Schmidt M, Koller R, Haviernik P, Watson R, Bies J, et al. Three genes with different functions in transformation are regulated by c-myb in myeloid cells. Blood Cells Mol Dis. 2001;27:483–8.

    Article  CAS  PubMed  Google Scholar 

  26. Blick M, Westin E, Gutterman J, Wong-Staal F, Gallo R, McCredie K, et al. Oncogene expression in human leukemia. Blood. 1984;64:1234–9.

    CAS  PubMed  Google Scholar 

  27. Gonda TJ. The c-myb oncoprotein. Int J Biochem Cell Biol. 1998;30:547–51.

    Article  CAS  PubMed  Google Scholar 

  28. Liang W. Age, sex and the risk of grade-specific second primary colorectal cancer: evidence for the protective effect of female hormone. Eur J Cancer. 2007;43:1856–61.

    Article  CAS  PubMed  Google Scholar 

  29. Yu Z, Li W, Liu F. Inhibition of proliferation and induction of apoptosis by genistein in colon cancer ht-29 cells. Cancer Lett. 2004;215:159–66.

    Article  CAS  PubMed  Google Scholar 

  30. Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS. Tissue distribution and quantitative analysis of estrogen receptor-alpha (eralpha) and estrogen receptor-beta (erbeta) messenger ribonucleic acid in the wild-type and eralpha-knockout mouse. Endocrinology. 1997;138:4613–21.

    Article  CAS  PubMed  Google Scholar 

  31. Kennelly R, Kavanagh DO, Hogan AM, Winter DC. Oestrogen and the colon: potential mechanisms for cancer prevention. Lancet Oncol. 2008;9:385–91.

    Article  CAS  PubMed  Google Scholar 

  32. Kuiper GG, Shughrue PJ, Merchenthaler I, Gustafsson JA. The estrogen receptor beta subtype: a novel mediator of estrogen action in neuroendocrine systems. Front Neuroendocrinol. 1998;19:253–86.

    Article  CAS  PubMed  Google Scholar 

  33. Ellem SJ, Risbridger GP. The dual, opposing roles of estrogen in the prostate. Ann N Y Acad Sci. 2009;1155:174–86.

    Article  CAS  PubMed  Google Scholar 

  34. Thornton MJ. The biological actions of estrogens on skin. Exp Dermatol. 2002;11:487–502.

    Article  CAS  PubMed  Google Scholar 

  35. Dechering K, Boersma C, Mosselman S. Estrogen receptors alpha and beta: two receptors of a kind? Curr Med Chem. 2000;7:561–76.

    CAS  PubMed  Google Scholar 

  36. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A. 1996;93:5925–30.

    Article  CAS  PubMed  Google Scholar 

  37. Tremblay GB, Tremblay A, Copeland NG, Gilbert DJ, Jenkins NA, Labrie F, et al. Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. Mol Endocrinol. 1997;11:353–65.

    Article  CAS  PubMed  Google Scholar 

  38. Mosselman S, Polman J, Dijkema R. Er beta: Identification and characterization of a novel human estrogen receptor. FEBS Lett. 1996;392:49–53.

    Article  CAS  PubMed  Google Scholar 

  39. Girdler F, Brotherick I. The oestrogen receptors (er alpha and er beta) and their role in breast cancer: a review. Breast. 2000;9:194–200.

    Article  CAS  PubMed  Google Scholar 

  40. Strobl JS, Wonderlin WF, Flynn DC. Mitogenic signal transduction in human breast cancer cells. Gen Pharmacol. 1995;26:1643–9.

    CAS  PubMed  Google Scholar 

  41. Verdier-Sevrain S, Yaar M, Cantatore J, Traish A, Gilchrest BA. Estradiol induces proliferation of keratinocytes via a receptor-mediated mechanism. Faseb J. 2004;18:1252–4.

    CAS  PubMed  Google Scholar 

  42. Qi X, Borowicz S, Pramanik R, Schultz RM, Han J, Chen G. Estrogen receptor inhibits c-jun-dependent stress-induced cell death by binding and modifying c-jun activity in human breast cancer cells. J Biol Chem. 2004;279:6769–77.

    Article  CAS  PubMed  Google Scholar 

  43. Ramsay RG, Gonda TJ. Myb function in normal and cancer cells. Nat Rev Cancer. 2008;8:523–34.

    Article  CAS  PubMed  Google Scholar 

  44. Thompson MA, Flegg R, Westin EH, Ramsay RG. Microsatellite deletions in the c-myb transcriptional attenuator region associated with over-expression in colon tumour cell lines. Oncogene. 1997;14:1715–23.

    Article  CAS  PubMed  Google Scholar 

  45. Jakacka M, Ito M, Weiss J, Chien PY, Gehm BD, Jameson JL. Estrogen receptor binding to DNA is not required for its activity through the nonclassical ap1 pathway. J Biol Chem. 2001;276:13615–21.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

H. Wilkins is the recipient of two Faculty Development Grants from Assumption College during 2005 and 2007. We wish to express our appreciation to D. Thornton and C. Restrepo for helpful technical support. We are also grateful for manuscript editing provided by R. Stottmann.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Heather R. Wilkins.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wilkins, H.R., Doucet, K., Duke, V. et al. Estrogen prevents sustained COLO-205 human colon cancer cell growth by inducing apoptosis, decreasing c-myb protein, and decreasing transcription of the anti-apoptotic protein bcl-2. Tumor Biol. 31, 16–22 (2010). https://doi.org/10.1007/s13277-009-0003-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-009-0003-2

Keywords

Navigation