Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Immortalization of epithelial progenitor cells mediated by resveratrol

Abstract

Within the hierarchy of epithelial stem cells, normal progenitor cells may express regulated telomerase during renewal cycles of proliferation and differentiation. Discontinuous telomerase activity may promote increased renewal capacity of progenitor cells, while deregulated/continuous telomerase activity may promote immortalization when differentiation and/or senescent pathways are compromised. In the present work, we show that resveratrol activates, while progesterone inactivates, continuous telomerase activity within 24 h in subpopulations of human Li–Fraumeni syndrome-derived breast epithelial cells. Resveratrol results in immortalization of mixed progenitor cells with mutant p53, but not human epithelial cells with wild type p53. Our results demonstrate the potential for renewing progenitor cells with mutant p53 to immortalize after continuous telomerase expression when exposed to certain environmental compounds. Understanding the effects of telomerase modulators on endogenous telomerase activity in progenitor cells is relevant to the role of immortalization in the initiation and progression of cancer subtypes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Bankfalvi A, Ludwig A, de-Hesselle B, Buerger H, Buchwalow IB, Boecker W . (2004). Different proliferative activity of the glandular and myoepithelial lineages in benign and proliferative and early malignant breast diseases. Modern Path 17: 1051–1061.

    Article  Google Scholar 

  • Bayne S, Liu JP . (2005). Hormones and growth factors regulate telomerase activity in ageing and cancer. Mol Cell Endocrinol 240: 11–22.

    Article  CAS  Google Scholar 

  • Bhat KP, Kosmeder II JW, Pezzuto JM . (2001). Biological effects of resveratrol. Antioxid Redox Signa 3: 1041–1064.

    Article  CAS  Google Scholar 

  • Bhat KPL, Pezzuto JM . (2002). Cancer chemopreventive activity of resveratrol. Ann NY Acad Sci 957: 210–229.

    Article  CAS  Google Scholar 

  • Campisi J . (2005). Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120: 513–522.

    Article  CAS  Google Scholar 

  • Conneely OM, Jericevic BM, Lydon JP . (2003). Progesterone receptors in mammary gland development and tumorigenesis. J Mamm Gland Biol Neopl 8: 205–214.

    Article  Google Scholar 

  • Counter CM, Hahn WC, Wei W, Caddle SD, Beijersbergen RL, Lansdorp PM et al. (1998). Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc Natl Acad Sci USA 95: 14723–14728.

    Article  CAS  Google Scholar 

  • Dimri G, Band H, Band V . (2005). Mammary epithelial cell transformation: insights from cell culture and mouse models. Breast Cancer Res 7: 171–179.

    Article  CAS  Google Scholar 

  • Dong CK, Masutomi K, Hahn WC . (2005). Telomerase: regulation, function and transformation. Crit Rev Oncol Hematol 54: 85–93.

    Article  Google Scholar 

  • Dong Z . (2003). Molecular mechanism of the chemopreventive effect of resveratrol. Mutat Res 523–524: 145–150.

    Article  Google Scholar 

  • Fridriksdottir AJ, Villadsen R, Gudjonsson T, Petersen OW . (2005). Maintenance of cell type diversification in the human breast. J Mammary Gland Biol Neoplasia 10: 61–74.

    Article  Google Scholar 

  • Gusman J, Malonne H, Atassi G . (2001). A reappraisal of the potential chemopreventive and chemotherapeutic properties of resveratrol. Carcinogenesis 22: 1111–1117.

    Article  CAS  Google Scholar 

  • Hahn WC . (2004). Cancer: surviving on the edge. Cancer Cell 6: 215–222.

    Article  CAS  Google Scholar 

  • Holt SE, Shay JW . (1999). Role of telomerase in cellular proliferation and cancer. J Cell Physiol 180: 10–18.

    Article  CAS  Google Scholar 

  • Kim H, Farris J, Christman SA, Kong BW, Foster LK, O'Grady SM et al. (2002). Events in the immortalizing process of primary human mammary epithelial cells by the catalytic subunit of human telomerase. Biochem J 365 (Part 3): 765–772.

    Article  CAS  Google Scholar 

  • Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL et al. (1994). Specific association of human telomerase activity with immortal cells and cancer. Science 266: 2011–2015.

    Article  CAS  Google Scholar 

  • Lanzilli G, Fuggetta MP, Tricarico M, Cottarelli A, Serafino A, Falchetti R et al. (2006). Resveratrol down-regulates the growth and telomerase activity of breast cancer cells in vitro. G Int J Oncol 28: 641–648.

    CAS  Google Scholar 

  • Le Corre L, Chalabi N, Delort L, Bignon YJ, Bernard-Gallon DJ . (2005). Resveratrol and breast cancer chemoprevention: molecular mechanisms. Mol Nutr Food Res 49: 462–471.

    Article  CAS  Google Scholar 

  • Lebeau J, Fouchet P, Ory K, Chevillard S . (2002). Down-regulation of telomerase activity after progesterone treatment of human breast cancer cells: essential role of cell cycle status. Anticancer Res 22: 2161–2166.

    CAS  PubMed  Google Scholar 

  • Leonhardt SA, Edwards DP . (2002). Mechanism of action of progesterone antagonists. Exp Biol Med (Maywood) 227: 969–980.

    Article  CAS  Google Scholar 

  • Leslie KK, Stein MP, Kumar NS, Dai D, Stephens J, Wandinger-Ness A et al. (2005). Progesterone receptor isoform identification and subcellular localization in endometrial cancer. Gyenol Oncol 96: 32–41.

    Article  CAS  Google Scholar 

  • Li X, O'Malley BW . (2003). Unfolding the action of progesterone receptors. J Biol Chem 278: 39261–39264.

    Article  CAS  Google Scholar 

  • Lim CS, Baumann CT, Htun H, Xian W, Irie M, Smith CL et al. (1999). Differential localization and activity of the A- and B-forms of the human progesterone receptor using green fluorescent protein chimeras. Mol Endocrinol 13: 366–375.

    Article  CAS  Google Scholar 

  • Masutomi K, Hahn WC . (2003). Telomerase and tumorigenesis. Cancer Lett 194: 163–172.

    Article  CAS  Google Scholar 

  • Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB et al. (2003). Telomerase maintains telomere structure in normal cells. Cell 114: 241–253.

    Article  CAS  Google Scholar 

  • Miloso M, Bertelli AA, Nicolini G, Tredici G . (1999). Resveratrol-induced activation of the mitogen-activated protein kinases, ERK1 and ERK2, in human neuroblastoma SH-SY5Y cells. Neurosci Lett 264: 141–144.

    Article  CAS  Google Scholar 

  • Moll UM, Ostermeyer AG, Haladay R, Winkfield B, Frazier M, Zambetti G . (1996). Cytoplasmic sequestration of wild-type p53 protein impairs the G1 checkpoint after DNA damage. Mol Cell Biol 16: 1126–1137.

    Article  CAS  Google Scholar 

  • Mote PA, Bartow S, Tran N, Clarke CL . (2002). Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Res Treat 72: 163–172.

    Article  CAS  Google Scholar 

  • Nikolaev AY, Li M, Puskas N, Qin J, Gu W . (2003). Parc: a cytoplasmic anchor for p53. Cell 112: 1–2.

    Article  Google Scholar 

  • Ostermeyer AG, Runko E, Winkfield B, Ahn B, Moll UM . (1996). Cytoplasmically sequestered wild-type p53 protein in neuroblastoma is relocated to the nucleus by a C-terminal peptide. Proc Natl Acad Sci USA 93: 15190–15194.

    Article  CAS  Google Scholar 

  • Petersen OW, Gudjonsson T, Villadsen R, Bissell MJ, Ronnov-Jessen L . (2003). Epithelial progenitor cell lines as models of normal breast morphogenesis and neoplasia. Cell Prolif 36: 33–44.

    Article  Google Scholar 

  • Rambhatla L, Bohn SA, Stadler PB, Boyd JT, Coss RA, Sherley JL . (2001). Cellular senescence: ex vivo p53-dependent asymmetric cell kinetics. J Biomed Biotechnol 1: 28–37.

    Article  CAS  Google Scholar 

  • Saeki Y, Tamura K, Yamamoto Y, Hatada T, Furuyama J, Utsunomiya J . (1997). Germline p53 mutation at codon 133 in a cancer-prone family. J Mol Med 75: 50–56.

    Article  CAS  Google Scholar 

  • Shay JW, Wright WE . (2005). Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 26: 867–874.

    Article  CAS  Google Scholar 

  • Shay JW, Tomlinson G, Piatyszek MA, Gollahon LS . (1995). Spontaneous in vitro immortalization of breast epithelial cells from a patient with Li-Fraumeni syndrome. Mol Cell Biol 15: 425–432.

    Article  CAS  Google Scholar 

  • Signorelli P, Ghidoni R . (2005). Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem 16: 449–466.

    Article  CAS  Google Scholar 

  • Stampfer MR, Garbe J, Nijjar T, Wigington D, Swisshelm K, Yaswen P . (2003). Loss of p53 function accelerates acquisition of telomerase activity in indefinite lifespan human mammary epithelial cell lines. Oncogene 22: 5238–5251.

    Article  CAS  Google Scholar 

  • Stingl J, Raouf A, Emerman JT, Eaves CJ . (2005). Epithelial progenitors in the normal human mammary gland. J Mammary Gland Biol Neoplasia 10: 49–59.

    Article  Google Scholar 

  • Sun W, Kang KS, Morita I, Trosko JE, Chang CC . (1999). High susceptibility of a human breast epithelial cell type with stem cell characteristics to telomerase activation and immortalization. Cancer Res 59: 6118–6123.

    CAS  PubMed  Google Scholar 

  • Tabata Y, Iizuka Y, Masuda NT, Shinei R, Kurihara K, Okonogi T et al. (2002). In vitro and in vivo characterization of novel nonsteroidal progesterone receptor antagonists derived from the fungal metabolite PF1092C. J Steroid Biochem Mol Biol 82: 217–223.

    Article  CAS  Google Scholar 

  • Tanaka M, Kyo S, Takakura M, Kanaya T, Sagawa T, Yamashita K et al. (1998). Expression of telomerase activity in human endometrium is localized to epithelial glandular cells and regulated in a menstrual phase-dependent manner correlated with cell proliferation. Am J Pathol 153: 1985–1991.

    Article  CAS  Google Scholar 

  • Trask D, Band V, Zajchowski DA, Yaswen P, Suh T, Sager R . (1990). Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells. Proc Natl Acad Sci USA 87: 2319–2323.

    Article  CAS  Google Scholar 

  • Wang Z, Kyo S, Takakura M, Tanaka M, Yatabe N, Maida Y et al. (2000). Progesterone regulates human telomerase reverse transcriptase gene expression via activation of mitogen-activated protein kinase signaling pathway. Cancer Res 60: 5376–5381.

    CAS  PubMed  Google Scholar 

  • Williams CD, Boggess JF, LaMarque LR, Meyer WR, Murray MJ, Fritz MA et al. (2001). A prospective, randomized study of endometrial telomerase during the menstrual cycle. J Clin Endocrinol Metab 86: 3912–3917.

    Article  CAS  Google Scholar 

  • Yaswen P, Stampfer M . (2002). Molecular changes accompanying senescence and immortalization of cultured human mammary epithelial cells. Int J Biochem Cell Biol 34: 1382–1394.

    Article  CAS  Google Scholar 

  • Yu CC, Lo SC, Wang TC . (2001). Telomerase is regulated by protein kinase C-zeta in human nasopharyngeal cancer cells. Biochem J 355: 459–464.

    Article  CAS  Google Scholar 

  • Zhivotovsky B, Kroemer G . (2004). Apoptosis and genomic instability. Nature Rev Mol Cell Biol 5: 752–762.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge Jackie Swanik for editorial comments and William Walker for technical assistance. This work was supported by NCI-NO1-CN43301, NCI-CN-05106, Lung Cancer SPORE P50 CA75907, NSCOR NNJ05HD36G and the Ted Nash Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J W Shay.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pearce, V., Sherrell, J., Lou, Z. et al. Immortalization of epithelial progenitor cells mediated by resveratrol. Oncogene 27, 2365–2374 (2008). https://doi.org/10.1038/sj.onc.1210886

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210886

Keywords

Search

Quick links