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:

Suppression of fatty acid synthase in MCF-7 breast cancer cells by tea and tea polyphenols: a possible mechanism for their hypolipidemic effects

ABSTRACT

Tea is a heavily consumed beverage world wide because of its unique aroma, less cost and broad availability. Fatty acid synthase (FAS) is a key enzyme in lipogenesis. FAS is overexpressed in the malignant human breast carcinoma MCF-7 cells and its expression is further enhanced by the epidermal growth factor (EGF). The EGF-induced expression of FAS was inhibited by green and black tea extracts. The expression of FAS was also suppressed by the tea polyphenol (−)-epigallocatechin 3-gallate (EGCG), theaflavin (TF-1), TF-2 and theaflavin 3,3′-digallate(TF-3) at both protein and mRNA levels that may lead to the inhibition of cell lipogenesis and proliferation. Both EGCG and TF-3 inhibit the activation of Akt and block the binding of Sp-1 to its target site. Furthermore, the EGF-induced biosyntheses of lipids and cell proliferation were significantly suppressed by EGCG and TF-3. These findings suggest that tea polyphenols suppress FAS expression by downregulating EGF receptor/PI3K/Akt/Sp-1 signal transduction pathway, and tea and tea polyphenols might induce hypolipidemic and antiproliferative effects by suppressing FAS.

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
Figure 6

Similar content being viewed by others

References

  1. Must A, Spadano J, Coakley EH, Field AE, Colditz G, Diets WH . The disease burden associated with overweight and obesity. JAMA 1999; 282: 1523–1529.

    Article  CAS  PubMed  Google Scholar 

  2. Halaas JL, Gajiwala KS, Maffei M, Sohen SL, Chait BT, Rabinowitz D et al. Weight reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543–546.

    Article  CAS  PubMed  Google Scholar 

  3. Smith S . The animal fatty acid synthase: one gene, one polypeptide, seven enzymes. FASEB J 1994; 8: 1248–1259.

    Article  CAS  PubMed  Google Scholar 

  4. Kuhajda FP . Fatty acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 2000; 16: 202–208.

    Article  CAS  PubMed  Google Scholar 

  5. Kuhajda FP, Pizer ES, Li JN, Mani NS, Frehywot GL, Townsend CA . Synthesis and anti-tumor activity of an inhibitor of fatty acid synthase. Proc Natl Acad Sci USA 2000; 97: 3450–3454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mobbs CV, Makimura H . Block the FAS, lose the fat. Nat Med 2002; 8: 335–336.

    Article  CAS  PubMed  Google Scholar 

  7. Loftus TM, Jarworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 2000; 288: 2379–2381.

    Article  CAS  PubMed  Google Scholar 

  8. Makimura H, Mizuno TM, Yang XJ, Silverstein J, Beasley J, Mobbs CV . Cerulenin mimics effects of leptin on metabolic rats, food intake, and body weight independent of the melanocortin system, but unlike leptin, cerulenin fails to block neuroendocrine effects of fasting. Diabetes 2001; 50: 733–739.

    Article  CAS  PubMed  Google Scholar 

  9. Bray GA . Drug treatment of obesity: don't throw out the baby with the bath water. Am J Clin Nutr 1998; 67: 1–2.

    Article  CAS  PubMed  Google Scholar 

  10. Lin YL, Cheng CY, Lin YP, Lau YW, Juan IM, Lin JK . Hypolipidemic effect of green tea leaves through induction of antioxidant and phase II enzymes including superoxide dismutase, catalase and glutathione S-transferase in rats. J Agric Food Chem 1998; 46: 1893–1899.

    Article  CAS  Google Scholar 

  11. Lee SF, Liang YC, Lin JK . Inhibition of 1,2,4-benzene triol generated active oxygen species and induction of phase II enzymes by green tea polyphenols. Chem Biol Interact 1995; 98: 283–301.

    Article  CAS  PubMed  Google Scholar 

  12. Yang TC, Kuo WL . Hypocholesterolemic effects of Chinese tea. Pharmacol Rev 1997; 35: 505–512.

    CAS  Google Scholar 

  13. Kao YH, Hiipakka RA, Liao S . Modulation of endocrine systems and food intake by green tea epigallocatechin 3-gallate. Endocrinology 2000; 141: 980–987.

    Article  CAS  PubMed  Google Scholar 

  14. Wang X, Tian W . Green tea epigallocatechin gallate: a natural inhibitor of fatty acid synthase. Biochem Biophys Res Commun 2001; 288: 1200–1206.

    Article  CAS  PubMed  Google Scholar 

  15. Li JN, Gorospe M, Chrest FJ, Kumaravel TS, Evans MK, Han WF et al. Pharmacological inhibition of fatty acid synthase activity produce both cytostatic and cytotoxic effects modulated by p53. Cancer Res 2001; 61: 1493–1499.

    CAS  PubMed  Google Scholar 

  16. Lin JK, Liang YC . Cancer chemoprevention of tea polyphenols. Proc Natl Res Counc ROC(B) 2000; 24: 1–13.

    Google Scholar 

  17. Lin JK, Liang YC, Lin-Shiau SY . Cancer chemoprevention by tea polyphenols through mitotic signal transduction blockade. Biochem Pharmacol 1999; 58: 911–915.

    Article  CAS  PubMed  Google Scholar 

  18. Yang YA, Han WF, Morin PJ, Chrest FJ, Pizer ES . Activation of fatty acid synthesis during neoplastic transformation: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Exp Cell Res 2002; 279: 80–90.

    Article  CAS  PubMed  Google Scholar 

  19. Vande Sande T, Shrijver ED, Heyns W, Verhoeven G, Swinnen JV . Role of the phosphatidylinositol 3′-kinase/PTEN/AKt kinase pathway in the overexpression of fatty acid synthase in LNCap prostate cencer cells. Cancer Res 2002; 62: 642–646.

    CAS  Google Scholar 

  20. Liang YC, Lin-Shiau SY, Chen CF, Lin JK . Suppression of extracellular signals and cell proliferation through EGF receptor binding by (−)-epigallocatechin 3-gallate in human A431 epidermoid carcinoma cells. J Cell Biochem 1997; 67: 55–65.

    Article  CAS  PubMed  Google Scholar 

  21. Kuhajda FP, Jenner K, Wood FD, Henniger RA, Jacobs LB, Dick JD et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci USA 1994; 91: 6379–6383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Swinner JV, Heemers H, Deboel L, Foufelle F, Heyns W, Verhoven G . Stimulation of tumor-associated fatty acid synthase expression by growth factor activation of the sterol regulatory element-binding protein pathway. Oncogene 2000; 19: 5173–5181.

    Article  Google Scholar 

  23. Blume-Jensen P, Hunter T . Oncogenic kinase signaling. Nature (Lond.) 2001; 411: 355–365.

    Article  CAS  Google Scholar 

  24. Wakil SJ, Stoops JK, Joshi VC . Fatty acid synthesis and its regulation. Ann Rev Biochem 1983; 52: 537–579.

    Article  CAS  PubMed  Google Scholar 

  25. Hillgartner FB, Salati LM, Goodridge AG . Physiological and molecular mechanisms involved in nutritional regulation of fatty acid synthesis. Physiol Rev 1995; 75: 47–76.

    Article  CAS  PubMed  Google Scholar 

  26. Moon YS, Latasa M, Griffin MJ, Sul HS . Suppression of fatty acid synthase promoter by polyunsaturated fatty acids. J Lipid Res 2002; 43: 691–698.

    CAS  PubMed  Google Scholar 

  27. Yang CS, Wang ZY . Tea and cancer. J Natl Cancer Inst 1993; 85: 1036–1049.

    Article  Google Scholar 

  28. Lin JK, Chen PC, Ho CT, Lin-Shiau SY . Inhibition of xanthine oxidase and suppression of intracellular reactive oxygen species in HL-60 cells by theaflavin 3,3′-digallate, (−)-epigallocatechin 3-gallate and propyl gallate. J Agric Food Chem 2000; 48: 2736–2743.

    Article  CAS  PubMed  Google Scholar 

  29. Pan MH, Liang YC, Lin-Shiau SY, Zhu NQ, Ho CT, Lin JK . Induction of apoptosis by the oolong tea polyphenol theasinensin A through cytochrome c release and activation of caspase-9 and caspase-3 in human U937 cells. J Agric Food Chem 2000; 48: 6337–6346.

    Article  CAS  PubMed  Google Scholar 

  30. Liang YC, Lin-Shiau SY, Chen CF, Lin JK . Inhibition of cyclin-dependent kinases 2 and 4 activities as well as induction of Cdk inhibitors p21 and p27 during growth arrest of human breast carcinoma cells by (−)-epigallocatechin 3-gallate. J Cell Biochem 1999; 75: 1–12.

    Article  CAS  PubMed  Google Scholar 

  31. Lin YL, Lin JK . (−)-Epigallocatechin 3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor NFκB. Mol Pharmacol 1997; 52: 465–472.

    Article  CAS  PubMed  Google Scholar 

  32. Lin JK . Cancer chemoprevention by tea polyphenols through modulating signal transduction pathways. Arch Pharm Res 2002; 25: 561–571.

    Article  CAS  PubMed  Google Scholar 

  33. Kusakabe T, Nashimoto A, Honma K, Suzuki T . Fatty acid synthase is highly expressed in carcinoma, adenoma, and in regenerative epithelium and intestinal metaplasia of the stomach. Histopathology 2002; 40: 71–79.

    Article  CAS  PubMed  Google Scholar 

  34. Pizer ES, Lax SF, Kuhajda FP, Pasternack GR, Kurman RJ . Fatty acid synthase expression in endometrial carcinoma: correlation with cell proliferation and hormone receptors. Cancer 1998; 83: 528–571.

    Article  CAS  PubMed  Google Scholar 

  35. Pardee AB . G1 events and regulation of cell proliferation. Science 1989; 246: 603–608.

    Article  CAS  PubMed  Google Scholar 

  36. Sporn MB . Carcinogenesis and cancer. Cancer Res 1991; 51: 6215–6218.

    CAS  PubMed  Google Scholar 

  37. Lazarov M, Kubo Y, Cai T, Dajee M, Tarutani M, Lin Q et al. CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis. Nat Med 2002; 8: 1105–1114.

    Article  CAS  PubMed  Google Scholar 

  38. Pawson T, Saxton TM . Signaling networks—do all roads lead to the same genes? Cell 1999; 97: 675–678.

    Article  CAS  PubMed  Google Scholar 

  39. Fambrough D, McClure K, Kazlauskas A, Lander ES . Diverse signaling pathways activated by growth factor receptors induce broadly overlapping, rather than independent, sets of genes. Cell 1999; 97: 727–741.

    Article  CAS  PubMed  Google Scholar 

  40. Pizer ES, Jackisch C, Wood FD, Pasternack GR, Davidson NE, Kuhajda FP . Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Res 1996; 56: 2745–2747.

    CAS  PubMed  Google Scholar 

  41. Katiyar SK, Afaq F, Azizuddin K, Mukhtar H . Inhibition of UVB-induced oxidative stress-mediated phosphorylation of mitogen-activated protein kinase signaling pathways in cultured human epidermal keratinocyte by green tea polyphenol (−)-epigallocatechin-3-gallate. Toxicol Appl Pharmacol 2001; 176: 110–117.

    Article  CAS  PubMed  Google Scholar 

  42. Chung JY, Park JO, Phyu H, Dong Z, Yang CS . Mechanism of inhibition of the Ras-MAP kinase signaling pathway in 30.76 Ras 12 cells by tea polyphenol (−)-epigallocatechin-3-gallate and theaflavin-3,3′-digallate. FASEB J 2001; 15: 2022–2024.

    Article  CAS  PubMed  Google Scholar 

  43. Nomura M, Kaji A, He Z, Ma WY, Miyamoto KI, Yang CS et al. Inhibitory mechanisms of tea polyphenols on the UVB- activated phosphatidyl-inositol 3-kinase pathway. J Biol Chem 2001; 276: 46624–46631.

    Article  CAS  PubMed  Google Scholar 

  44. Chen RH, Chang MC, Su YH, Tsai YT, Kuo ML . Interleukin-6 inhibits transforming growth factor-β-induced apoptosis through the phosphatidylinositol 3-kinase/Akt and signal transducers and activators of transcription 3 pathways. J Biol Chem 1999; 274: 23013–23019.

    Article  CAS  PubMed  Google Scholar 

  45. Pizer ES, Wood FD, Pasternock GR, Kuhajda FP . Fatty acid synthase (FAS): a target for cytotoxic antimetabolites in HL-60 promyelocytic leukemia cells. Cancer Res 1996; 56: 745–751.

    CAS  PubMed  Google Scholar 

  46. Kanazawa T, Izawa M, Kaneko H, Onodera K, Metoki H, Oike Y et al. Comparison among lipid constituents in native LDL, ultra-water-soluble LDL, and vessel wall and their significance in arteriosclerosis. Exp Mol Pathol 1987; 47: 166–174.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Science Council NSC 91-2320-B-002-068 and NSC 91-2311-B-002-037, by the National Health Research Institute NHRI-EX91-8913BL.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J-K Lin.

Additional information

DUALITY OF INTEREST

None declared.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yeh, CW., Chen, WJ., Chiang, CT. et al. Suppression of fatty acid synthase in MCF-7 breast cancer cells by tea and tea polyphenols: a possible mechanism for their hypolipidemic effects. Pharmacogenomics J 3, 267–276 (2003). https://doi.org/10.1038/sj.tpj.6500192

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500192

Keywords

This article is cited by

Search

Quick links