Skip to main content
SpringerLink
Log in

2ME and 2OHE2 exhibit growth inhibitory effects and cell cycle arrest at G2/M in RL95-2 human endometrial cancer cells through activation of p53 and Chk1

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Evidence is accumulating that estradiol (E2) may play a dual role in carcinogenic and anticarcinogenic effects by different metabolic pathways. It has been shown that some metabolites of E2 exert proliferative and others anti-proliferative properties on human cancer cells. In the present study, the effects of E2 and its four primary metabolites including 2-hydroxyestradiol (2OHE2), 4-hydroxyestradiol (4OHE2), 2-methoxyestradiol (2ME), and 4-methoxyestradiol (4ME) on proliferation and cell cycle in RL95-2 human endometrial cells were investigated. Our results indicate that 2ME and 2OHE2, but not E2, 4ME, and 4OHE2, exhibit the inhibitory effect through cell cycle arrest at G2/M. 2ME and 2OHE2-induced G2/M cell cycle arrest associated with activation of p53 (Ser15), upregulation of p21WAF1/Cip1 (p21) and GADD45, inactivation of Cdc2 (Tyr15), as well as downregulation of Cyclin B1. 2ME and 2OHE2-mediated cell cycle arrest at G2/M was also related to activation of protein kinase Chk1 which is associated with p53 (Ser20) activation and downstream responses.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. American Cancer Society (2009) Cancer facts and figures. American Cancer Society, Atlanta, p 2009

    Google Scholar 

  2. Zhu BT, Lee AJ (2005) NADPH-dependent metabolism of 17β-estradiol and estrone to polar and nonpolar metabolites by human tissues and cytochrome P450 isoforms. Steroids 70:225–244

    Article  PubMed  CAS  Google Scholar 

  3. Martucci CP, Fishman J (1993) P450 enzymes of estrogen metabolism. Pharmacol Ther 57:237–257

    Article  PubMed  CAS  Google Scholar 

  4. Tsuchiya Y, Nakajima M, Yokoi T (2005) Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett 227:115–124

    Article  PubMed  CAS  Google Scholar 

  5. Parl FF, Egan KM, Li C, Crooke PS (2009) Estrogen exposure, metabolism, and enzyme variants in a model for breast cancer risk prediction. Cancer Inform 7:109–121

    PubMed  CAS  Google Scholar 

  6. Zhao Z, Kosinska W, Khmelnitsky M, Cavalieri EL, Rogan EG, Chakravarti D, Sacks PG, Guttenplan JB (2006) Mutagenic activity of 4-hydroxyestradiol, but not 2-hydroxyestradiol, in BB rat embryonic cells, and the mutational spectrum of 4-hydroxyestradiol. Chem Res Toxicol 19:475–479

    Article  PubMed  CAS  Google Scholar 

  7. Qadan LR, Perez-Stable CM, Anderson C, D’Ippolito G, Herron A, Howard GA, Roos BA (2001) 2-Methoxyestradiol induces G2/M arrest and apoptosis in prostate cancer. Biochem Biophys Res Commun 285:1259–1266

    Article  PubMed  CAS  Google Scholar 

  8. Mabjeesh NJ, Escuin D, LaVallee TM, Pribluda VS, Swartz GM, Johnson MS, Willard MT, Zhong H, Simons JW, Giannakakou P (2003) 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell 3:363–375

    Article  PubMed  CAS  Google Scholar 

  9. Gupta M, McDougal A, Safe S (1998) Estrogenic and antiestrogenic activities of 16alpha- and 2-hydroxy metabolites of 17beta-estradiol in MCF-7 and T47D human breast cancer cells. J Steroid Biochem Mol Biol 67:413–419

    Article  PubMed  CAS  Google Scholar 

  10. Levine AJ, Oren M (2009) The first 30 years of p53: growing ever more complex. Nat Rev Cancer 9:749–758

    Article  PubMed  CAS  Google Scholar 

  11. Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137:413–431

    Article  PubMed  CAS  Google Scholar 

  12. Taylor WR, Stark GR (2001) Regulation of the G2/M transition by p53. Oncogene 20:1803–1815

    Article  PubMed  CAS  Google Scholar 

  13. Wang XW, Zhan Q, Coursen JD, Khan MA, Kontny HU, Yu L et al (1999) GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci USA 96:3706–3711

    Article  PubMed  CAS  Google Scholar 

  14. Krause K, Wasner M, Reinhard W, Haugwitz U, Dohna CL, Mossner J (2000) The tumour suppressor protein p53 can repress transcription of cyclin B. Nucleic Acids Res 28:4410–4418

    Article  PubMed  CAS  Google Scholar 

  15. Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F (2000) Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint. Genes Dev 14:1448–1459

    Article  PubMed  CAS  Google Scholar 

  16. Furnari B, Rhind N, Russell P (1997) Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint kinase. Science 277:1495–1497

    Article  PubMed  CAS  Google Scholar 

  17. Shieh SY, Ahn J, Tamai K, Taya Y, Prives C (2000) The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 14:289–300

    PubMed  CAS  Google Scholar 

  18. Tian H, Faje AT, Lee SL, Jorgensen TJ (2002) Radiation-induced phosphorylation of Chk1 at S345 is associated with p53-dependent cell cycle arrest pathways. Neoplasia 4:171–180

    Article  PubMed  CAS  Google Scholar 

  19. Kato S, Sadarangani A, Lange S, Villalon M, Branes J, Brosens JJ, Owen GI, Cuello M (2007) The oestrogen metabolite 2-methoxyoestradiol alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand mediates apoptosis in cancerous but not healthy cells of the human endometrium. Endocr Relat Cancer 14:351–368

    Article  PubMed  CAS  Google Scholar 

  20. Gao N, Budhraja A, Cheng S, Yao H, Zhang Z, Shi X (2009) Induction of apoptosis in human leukemia cells by grape seed extract occurs via activation of c-Jun NH2-terminal kinase. Clin Cancer Res 15:140–149

    Article  PubMed  CAS  Google Scholar 

  21. Carter J, Pather S (2006) An overview of uterine cancer and its management. Exp Rev Anticancer Ther 6:33–42

    Article  Google Scholar 

  22. Schutze N, Vollmer G, Tiemann I, Geiger M, Knuppen R (1993) Catecholestrogens are MCF-7 cell estrogen receptor agonists. J Steroid Biochem Mol Biol 46:781–789

    Article  PubMed  CAS  Google Scholar 

  23. Seeger H, Wallwiener D, Kraemer E, Mueck AO (2006) Comparison of possible carcinogenic estradiol metabolites: effects on proliferation, apoptosis and metastasis of human breast cancer cells. Maturitas 54:72–77

    Article  PubMed  CAS  Google Scholar 

  24. Fotsis T, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP, Schweigerer L (1994) The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature 368:237–239

    Article  PubMed  CAS  Google Scholar 

  25. Ball P, Knuppen R (1980) Catecholoestrogens (2- and 4-hydroxyestrogens): chemistry, biogenesis, metabolism, occurrence and physiological significance. Acta Endocrinol Suppl (Copenh) 232:1–127

    CAS  Google Scholar 

  26. Sherr CJ (1996) Cancer cell cycles. Science 274:1672–1677

    Article  PubMed  CAS  Google Scholar 

  27. Boulaire J, Fotedar A, Fotedar R (2000) The functions of the cdk-cyclin kinase inhibitor p21WAF1. Pathol Biol (Paris) 48:190–202

    CAS  Google Scholar 

  28. Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC, Fornace AJ Jr (1999) Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 18:2892–2900

    Article  PubMed  CAS  Google Scholar 

  29. Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15:2177–2196

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by the National Science Foundation of China (No. 30971288).

Author information

Authors and Affiliations

  1. Department of Nutrition, Southwest Hospital, 3rd Military Medical University, Chongqing, China

    Qian-fen Gong & Rong Xin

  2. Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China

    E-hu Liu, Xiuning Huang & Ning Gao

Authors
  1. Qian-fen Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E-hu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rong Xin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiuning Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ning Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ning Gao.

Additional information

Qian-fen Gong and E-hu Liu contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gong, Qf., Liu, Eh., Xin, R. et al. 2ME and 2OHE2 exhibit growth inhibitory effects and cell cycle arrest at G2/M in RL95-2 human endometrial cancer cells through activation of p53 and Chk1. Mol Cell Biochem 352, 221–230 (2011). https://doi.org/10.1007/s11010-011-0757-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-0757-x

Keywords

Search

Navigation