Skip to main content

Advertisement

SpringerLink
Log in

Adenosine monophosphate activated protein kinase (AMPK), a mediator of estradiol-induced apoptosis in long-term estrogen deprived breast cancer cells

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Estrogens stimulate growth of hormone-dependent breast cancer but paradoxically induce tumor regress under certain circumstances. We have shown that long-term estrogen deprivation (LTED) enhances the sensitivity of hormone dependent breast cancer cells to estradiol (E2) so that physiological concentrations of estradiol induce apoptosis in these cells. E2-induced apoptosis involve both intrinsic and extrinsic pathways but precise mechanisms remain unclear. We found that exposure of LTED MCF-7 cells to E2 activated AMP activated protein kinase (AMPK). In contrast, E2 inhibited AMPK activation in wild type MCF-7 cells where E2 prevents apoptosis. As a result of AMPK activation, the transcriptional activity of FoxO3, a downstream factor of AMPK, was up-regulated in E2 treatment of LTED. Increased activity of FoxO3 was demonstrated by up-regulation of three FoxO3 target genes, Bim, Fas ligand (FasL), and Gadd45α. Among them, Bim and FasL mediate intrinsic and extrinsic apoptosis respectively and Gadd45α causes cell cycle arrest at the G2/M phase. To further confirm the role of AMPK in apoptosis, we used AMPK activator AICAR in wild type MCF-7 cells and examined apoptosis, proliferation and expression of Bim, FasL, and Gadd45α. The effects of AICAR on these parameters recapitulated those observed in E2-treated LTED cells. Activation of AMPK by AICAR also increased expression of Bax in MCF-7 cells and its localization to mitochondria, which is a required process for apoptosis. These results reveal that AMPK is an important factor mediating E2-induced apoptosis in LTED cells, which is implicative of therapeutic potential for relapsing breast cancer after hormone therapy.

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

Similar content being viewed by others

References

  1. Yue W, Wang J-P, Conaway MR, Li Y, Santen RJ (2003) Adaptive hypersensitivity following long-term estrogen deprivation: involvement of multiple signal pathways. J Steroid Biochem Mol Biol 86:265–274

    Article  CAS  PubMed  Google Scholar 

  2. Masamura S, Santner SJ, Heitjan DF, Santen RJ (1995) Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells. J Clin Endocrinol Metab 80(10):2918–2925

    CAS  PubMed  Google Scholar 

  3. Song RX-D, Mor G, Naftolin F, McPherson RA, Song J, Zhang Z, Yue W, Wang J-P, Santen RJ (2001) Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17β-estradiol. J Natl Cancer Inst 93(22):1714–1723

    Article  CAS  PubMed  Google Scholar 

  4. Lewis JS, Meeke K, Osipo C, Ross EA, Kidawi N, Li T, Bell E, Chandel NS, Jordan VC (2005) Intrinsic mechanism of estradiol-Induced apoptosis in breast cancer cells resistant to estrogen deprivation. J Natl Cancer Inst 97(23):1746–1759

    Article  CAS  PubMed  Google Scholar 

  5. Carter AC, Sedransk N, Kelley RM et al (1977) Diethylstilbestrol: recommended dosages for different categories of breast cancer patients: report of the cooperative breast cancer group. JAMA 237(19):2079–2085. doi:10.1001/jama.1977.03270460065023

    Article  CAS  PubMed  Google Scholar 

  6. Yue W, Wang J-P, Zhang L, Wang W, Santen RJ, Aiyar SE (2013) Induction of apoptosis in hormone refractory breast cancer: horizontal modulation is superior to vertical. J Exp Ther Oncol 10:16–179

    Google Scholar 

  7. Greer EL, Brunet A (2005) FOXO transcription factors at the interface between longevity and tumor suppresion. Oncogene 24:7410–7425

    Article  CAS  PubMed  Google Scholar 

  8. Zhang Y, Gan B, Liu D, J-h Paik (2011) FoxO family members in cancer. Cancer Biol Ther 12:253–259

    Article  CAS  PubMed  Google Scholar 

  9. Brunet A, Bonni A, Zigmond MJ, Lin M, Juo ZP, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell Cycle 96:857–868

    CAS  Google Scholar 

  10. Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP, Brunet A (2007) The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282:30107–30119

    Article  CAS  PubMed  Google Scholar 

  11. Hu MCT, Lee D-F, Xia W, Golfman LS, Ou-Yang F, Yang J-Y, Zou Y, Bao S, Hanada N, Saso H, Kobayashi R, Hung M-C (2004) IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117(2):225–237. doi:10.1016/S0092-8674(04)00302-2

    Article  CAS  PubMed  Google Scholar 

  12. Yang J-Y, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, Lang J-Y, Lai C-C, Chang C-J, Huang W-C, Huang H, Kuo H-P, Lee D-F, Li L-Y, Lien H-C, Cheng X, Chang K-J, Hsiao C-D, Tsai F-J, Tsai C-H, Sahin AA, Muller WJ, Mills GB, Yu D, Hortobagyi GN, Hung M-C (2008) ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 10(2):138–148. http://www.nature.com/ncb/journal/v10/n2/suppinfo/ncb1676_S1.html

  13. Kim J-H, Choi S-Y, Kang B-H, Lee S-M, Park HS, Kang G-Y, Bang JY, Cho E-J, Youn H-D (2013) AMP-activated protein kinase phosphorylates CtBP1 and down-regulates its activity. Biochem Biophys Res Commun 431:8–13

    Article  CAS  PubMed  Google Scholar 

  14. Jiang S-y, Wolf DM, Yingling JM, Chang C, Jordan VC (1992) An estrogen receptor positive MCF-7 clone that is resistant to antiestrogens and estradiol. Mol Cell Endocrinol 90(1):77–86. doi:10.1016/0303-7207(92)90104-E

    Article  CAS  PubMed  Google Scholar 

  15. Pathiraja TN, Nayak SR, Xi Y, Jiang S, Garee JP, Edwards DP, Lee AV, Chen J, Shea MJ, Santen RJ, Gannon F, Kangaspeska S, Jelinek J, Issa J-PJ, Richer JK, Elias A, McIlroy M, Young LS, Davidson NE, Schiff R, Li W, Oesterreich S (2014) Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer. Sci Transl Med 6(229):229ra241. doi:10.1126/scitranslmed.3008326

    Article  Google Scholar 

  16. Chan CM, Martin LA, Johnston SR, Ali S, Dowsett M (2002) Molecular changes associated with the acquisition of oestrogen hypersensitivity in MCF-7 breast cancer cells on long-term oestrogen deprivation. J Steroid Biochem Mol Biol 81:333–341

    Article  CAS  PubMed  Google Scholar 

  17. Hardie DG, Scott JW, Pan DA, Hudson ER (2003) Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 546(1):113–120. doi:10.1016/S0014-5793(03)00560-X

    Article  CAS  PubMed  Google Scholar 

  18. Kemp BE, Stapleton D, Campbell DJ, Chen ZP, Murthy S, Walter M, Gupta A, Adams JJ, Katsis F, van Denderen B, Jennings IG, Iseli T, Michell BJ, Witters LA (2003) AMP-activated protein kinase, super metabolic regulator. Biochem Soc Trans 31:162–168

    Article  CAS  PubMed  Google Scholar 

  19. Towler MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100:328–341

    Article  CAS  PubMed  Google Scholar 

  20. Meisse D, Van de Casteele M, Beauloye C, Hainault I, Kefas BA, Rider MH, Foufelle F, Hue L (2002) Sustained activation of AMP-activated protein kinase induces c-Jun N-terminal kinase activation and apoptosis in liver cells. FEBS Lett 526:38–42

    Article  CAS  PubMed  Google Scholar 

  21. Sauer H, Engel S, Milosevic N, Sharifpanah F, Wartenberg M (2012) Activation of AMP-kinase by AICAR induces apoptosis of DU-145 prostate cancer cells through generation of reactive oxygen species and activation of c-Jun N-terminal kinase. Int J Oncol 40:501–508

    CAS  PubMed  Google Scholar 

  22. Lee K-H, Hsu E-C, Guh J-H, Yang H-C, Wang D, Kulp SK, Shapiro CL, Chen C-S (2011) Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator. J Biol Chem 286(45):39247–39258

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Brown KA, McInnes KJ, Takagi K, Ono K, Hunger N, Wang L, Sasano H, Simpson ER (2011) LKB1 expression is inhibited by estradiol-17β in MCF-7 cells. J Steroid Biochem Mol Biol 127:439–443

    Article  CAS  PubMed  Google Scholar 

  24. Gilley J, Coffer PJ, Ham J (2003) FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 162(4):613–622

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Dijkers PF, Medema RH, Lammers J-WJ, Koenderman L, Coffer PJ (2000) Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 10:1201–1204

    Article  CAS  PubMed  Google Scholar 

  26. Sunters A, de Mattos SF, Stahl M, Brosens JJ, Zoumpoulidou G, Saunders CA, Coffer PJ, Medema BH, Coombes RC, Lam EW-F (2003) FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem 278:49795–49805

    Article  CAS  PubMed  Google Scholar 

  27. Song RX-D, Chen Y, Zhang Z, Bao Y, Yue W, Wang J, Fan P, Santen RJ (2010) Estrogen utilization of IGF-1-R and EGF-R to signal in breast cancer cells. J Steroid Biochem Mol Biol 118:219–230

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Grooteclaes M, Deveraux Q, Hildebrand J, Zhang Q, Goodman RH, Frisch SM (2003) C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs. Proc Natl Acad Sci USA 100:4568–4573

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Cook KL, Shajahan AN, Wärri A, Jin L, Hilakivi-Clarke LA, Clarke R (2012) Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness. Cancer Res 72:3337–3349

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Cook KL, Wärri A, Soto-Pantoja DR, Clarke PA, Cruz MI, Zwart A, Clarke R (2014) Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer. Clin Cancer Res 20(12):3222–3232. doi:10.1158/1078-0432.CCR-13-3227

    Article  CAS  PubMed  Google Scholar 

  31. Yue W, Fan P, Wang J-P, Li Y, Santen RJ (2007) Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells. J Steroid Biochem Mol Biol 106:102–110

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The current studies were supported by Department of Defense Grant (W81XWH-10-1-0030). The authors acknowledge Dr. Craig Jordan for providing MCF-7-5C cells.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Author notes

  1. Haiyan Chen

    Present address: Department of Hematology, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, No. 6, Fangxinyuan, Fengtai District, Beijing, 100078, China

Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, P. O. Box 801416, Charlottesville, VA, 22908, USA

    Haiyan Chen, Ji-ping Wang, Richard J. Santen & Wei Yue

Authors
  1. Haiyan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ji-ping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard J. Santen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei Yue.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 1087 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, H., Wang, Jp., Santen, R.J. et al. Adenosine monophosphate activated protein kinase (AMPK), a mediator of estradiol-induced apoptosis in long-term estrogen deprived breast cancer cells. Apoptosis 20, 821–830 (2015). https://doi.org/10.1007/s10495-015-1111-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-015-1111-7

Keywords

Search

Navigation