Skip to main content

Advertisement

Log in

Inhibition of leptin gene expression and secretion by silibinin: possible role of estrogen receptors

  • Original Research
  • Published:
Cytotechnology Aims and scope Submit manuscript

Abstract

Leptin plays the role of mitogenic factor in the breast carcinogenesis. Therefore, it could be considered as a target for breast cancer therapy. Leptin gene expression could be modulated by activation of estrogen receptors. Silibinin is an herbal compound with anti-cancer activity on prostate and colorectal cancers. Based on the fact that targeting of leptin can be considered as a novel strategy for breast cancer therapy, the aim of this study was the investigation of potentiality of silibinin for inhibition of leptin gene expression and secretion, and its link with expression of estrogen receptors. Cytotoxic effect of silibinin on T47D breast cancer cells was investigated by MTT assay test after 24, 48 and 72 h treatments with different concentrations of silibinin. The levels of leptin, estrogen receptor α and estrogen receptor β genes expression was measured by reverse-transcription real-time PCR. The amount of secreted leptin in the culture medium was determined by ELISA. Data were statistically analyzed by one-way ANOVA test. Silibinin inhibits growth of T47D cells in a time and dose dependent manner. There was significant difference between control and treated cells in the levels of leptin, estrogen receptor β expression levels and the quantity of secreted leptin was decreased in the treated cells in comparison to control cells. In conclusion, silibinin inhibits the expression and the secretion of leptin and in the future it might probably be a drug candidate for breast cancer therapy through leptin targeting.

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

Similar content being viewed by others

References

  • Collins S, Kuhn CM, Petro AE, Swick AG, Chrunyk BA, Surwit RS (1996) Role of leptin in fat regulation. Nature 380:677

    Article  CAS  Google Scholar 

  • Dieudonne MN, Machinal-Quelin F, Serazin-Leroy V, Leneveu MC, Pecquery R, Giudicelli Y (2002) Leptin mediates a proliferative response in human MCF7 breast cancer cells. Biochem Biophys Res Commun 293:622–628

    Article  CAS  Google Scholar 

  • Fantuzzi G, Faggioni R (2000) Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 68:437–446

    CAS  Google Scholar 

  • Fazeli M, Zarkesh-Esfahani H, Wu Z, Maamra M, Bidlingmaier M, Pockley AG, Watson P, Matarese G, Strasburger CJ, Ross RJ (2006) Identification of a monoclonal antibody against the leptin receptor that acts as an antagonist and blocks human monocyte and T cell activation. J Immunol Methods 312:190–200

    Article  CAS  Google Scholar 

  • Garofalo C, Surmacz E (2006) Leptin and cancer. J Cell Physiol 207:12–22

    Article  CAS  Google Scholar 

  • Gonzalez RR, Watters A, Xu Y, Singh UP, Mann DR, Rueda BR, Penichet ML (2009) Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer. Breast Cancer Res 11:R36

    Article  Google Scholar 

  • Hardwick JC, Van Den Brink GR, Offerhaus GJ, Van Deventer SJ, Peppelenbosch MP (2001) Leptin is a growth factor for colonic epithelial cells. Gastroenterology 121:79–90

    Article  CAS  Google Scholar 

  • Hu X, Juneja SC, Maihle NJ, Cleary MP (2002) Leptin—a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 94:1704–1711

    Article  CAS  Google Scholar 

  • Ishikawa M, Kitayama J, Nagawa H (2004) Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res 10:4325–4331

    Article  CAS  Google Scholar 

  • Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics 2010. CA Cancer J Clin 60:277–300

    Article  Google Scholar 

  • Kaur M, Agarwal R (2007) Silymarin and epithelial cancer chemoprevention: how close we are to bedside? Toxicol Appl Pharmacol 224:350–359

    Article  CAS  Google Scholar 

  • Koda M, Sulkowska M, Kanczuga-Koda L, Jarzabek K, Sulkowski S (2007) Expression of leptin and its receptor in female breast cancer in relation with selected apoptotic markers. Folia Histochem Cytobiol 45:S187–S191

    Google Scholar 

  • Laud K, Gourdou I, Pessemesse L, Peyrat JP, Djiane J (2002) Identification of leptin receptors in human breast cancer: functional activity in the T47-D breast cancer cell line. Mol Cell Endocrinol 188:219–226

    Article  CAS  Google Scholar 

  • Lin CJ, Sukarieh R, Pelletier J (2009) Silibinin inhibits translation initiation: implications for anticancer therapy. Mol Cancer Ther 8:1606–1612

    Article  CAS  Google Scholar 

  • Liu Z, Uesaka T, Watanabe H, Kato N (2001) High fat diet enhances colonic cell proliferation and carcinogenesis in rats by elevating serum leptin. Int J Oncol 19:1009–1014

    CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408

    Article  CAS  Google Scholar 

  • Löffler S, Aust G, Köhler U, Spanel-Borowski K (2001) Evidence of leptin expression in normal and polycystic human ovaries. Mol Hum Reprod 7:1143–1149

    Article  Google Scholar 

  • Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, Nakao K (1997) Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 3:1029–1033

    Article  CAS  Google Scholar 

  • Mix H, Widjaja A, Jandl O, Cornberg M, Kaul A, Göke M, Beil W, Kuske M, Brabant G, Manns MP, Wagner S (2000) Expression of leptin and leptin receptor isoforms in the human stomach. Gut 47:481–486

    Article  CAS  Google Scholar 

  • Morroni M, De Matteis R, Palumbo C, Ferretti M, Villa I, Rubinacci A, Cinti S, Marotti G (2004) In vivo leptin expression in cartilage and bone cells of growing rats and adult humans. J Anat 205:291–296

    Article  CAS  Google Scholar 

  • O’Neil JS, Burow ME, Green AE, McLachlan JA, Henson MC (2001) Effects of estrogen on leptin gene promoter activation in MCF-7 breast cancer and JEG-3 choriocarcinoma cells: selective regulation via estrogen receptors alpha and beta. Mol Cell Endocrinol 176:67–75

    Article  Google Scholar 

  • Oda A, Taniguchi T, Yokoyama M (2001) Leptin stimulates rat aortic smooth muscle cell proliferation and migration. Kobe J Med Sci 47:141–150

    CAS  Google Scholar 

  • Peters JH, Simasko SM, Ritter RC (2007) Leptin analog antagonizes leptin effects on food intake and body weight but mimics leptin-induced vagal afferent activation. Endocrinology 148:2878–2885

    Article  CAS  Google Scholar 

  • Pourhassan M, Zarghami N, Rahmati M, Alibakhshi A, Ranjbari R (2010) The inhibitory effect of Curcuma longa extract on telomerase activity in A549 lung cancer cell line. Afr J Biotechnol 9:912–919

    Google Scholar 

  • Ray A, Cleary MP (2010) Leptin as a potential therapeutic target for breast cancer prevention and treatment. Expert Opin Ther Targets 14:443–451

    Article  CAS  Google Scholar 

  • Seidlová-Wuttke D, Becker T, Christoffel V, Jarry H, Wuttke W (2003) Silymarin is a selective estrogen receptor beta (ERbeta) agonist and has estrogenic effects in the metaphysis of the femur but no or antiestrogenic effects in the uterus of ovariectomized (ovx) rats. J Steroid Biochem Mol Biol 86:179–188

    Article  Google Scholar 

  • Shin JH, Hur JY, Seo HS, Jeong YA, Lee JK, Oh MJ, Kim T, Saw HS, Kim SH (2007) The ratio of estrogen receptor alpha to estrogen receptor beta in adipose tissue is associated with leptin production and obesity. Steroids 72:592–599

    Article  CAS  Google Scholar 

  • Singh RP, Sharma G, Dhanalakshmi S, Agarwal C, Agarwal R (2009) Suppression of advanced human prostate tumor growth in athymic mice by silibinin feeding is associated with reduced cell proliferation, increased apoptosis, and inhibition of angiogenesis. Mol Cancer Ther 8:1606–1612

    Article  Google Scholar 

  • Solberg R, Aas V, Thoresen GH, Kase ET, Drevon CA, Rustan AC, Reseland JE (2005) Leptin expression in human primary skeletal muscle cells is reduced during differentiation. J Cell Biochem 96:89–96

    Article  CAS  Google Scholar 

  • Soyupek S, Armağan A, Serel TA, Hoşcan MB, Perk H, Karaöz E, Candir O (2005) Leptin expression in the testicular tissue of fertile and infertile men. Arch Androl 51:239–246

    Article  CAS  Google Scholar 

  • Tartaglia LA (1997) The leptin receptor. J Biol Chem 272:6093–6096

    CAS  Google Scholar 

  • Tiwari P, Kumar A, Balakrishnan S, Kushwaha HS, Mishra KP (2011) Silibinin-induced apoptosis in MCF7 and T47D human breast carcinoma cells involves caspase-8 activation and mitochondrial pathway. Cancer Invest 29:12–20

    Article  CAS  Google Scholar 

  • Vona-Davis L, Rose DP (2007) Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 14:189–206

    Article  CAS  Google Scholar 

  • Yi KW, Shin JH, Seo HS, Lee JK, Oh MJ, Kim T, Saw HS, Kim SH, Hur JY (2008) Role of estrogen receptor-alpha and -beta in regulating leptin expression in 3T3-L1 adipocytes. Obesity (Silver Spring) 16:2393–2399

    Article  CAS  Google Scholar 

  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Tuberculosis and Lung Disease Research Center for granting of this work and also Drug Applied Research Center for technical assistance. Both of these centers are affiliated to Tabriz University of Medical Sciences, Tabriz, Iran. The authors declare that the abstract of current work has been presented as poster at “First international meeting on Cellular and Molecular Advances in Non-Contagious Diseases (May 2011, Babol City, Iran)” and published in the meeting journal (Cell Journal, Vol. 13, Supplement 2).

Conflict of interest

The authors have no competing interests.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nosratollah Zarghami.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nejati-Koshki, K., Zarghami, N., Pourhassan-Moghaddam, M. et al. Inhibition of leptin gene expression and secretion by silibinin: possible role of estrogen receptors. Cytotechnology 64, 719–726 (2012). https://doi.org/10.1007/s10616-012-9452-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10616-012-9452-3

Keywords

Navigation