Breast Cancer Research and Treatment

, Volume 130, Issue 2, pp 387–398 | Cite as

Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase

  • Puspa R. Pandey
  • Hiroshi Okuda
  • Misako Watabe
  • Sudha K. Pai
  • Wen Liu
  • Aya Kobayashi
  • Fei Xing
  • Koji Fukuda
  • Shigeru Hirota
  • Tamotsu Sugai
  • Go Wakabayashi
  • Keisuke Koeda
  • Masahiro Kashiwaba
  • Kazuyuki Suzuki
  • Toshimi Chiba
  • Masaki Endo
  • Tomoaki Fujioka
  • Susumu Tanji
  • Yin-Yuan Mo
  • Deliang Cao
  • Andrew C. Wilber
  • Kounosuke Watabe
Preclinical Study

Abstract

Resveratrol is a natural polyphenolic compound and has been shown to exhibit cardio-protective as well as anti-neoplastic effects on various types of cancers. However, the exact mechanism of its anti-tumor effect is not clearly defined. Resveratrol has been shown to have strong hypolipidemic effect on normal adipocytes and as hyper-lipogenesis is a hallmark of cancer cell physiology, the effect of resveratrol on lipid synthesis in cancer stem-like cells (CD24/CD44+/ESA+) that were isolated from both ER+ and ER− breast cancer cell lines was examined. The authors found that resveratrol significantly reduced the cell viability and mammosphere formation followed by inducing apoptosis in cancer stem-like cells. This inhibitory effect of resveratrol is accompanied by a significant reduction in lipid synthesis which is caused by the down-regulation of the fatty acid synthase (FAS) gene followed by up-regulation of pro-apoptotic genes, DAPK2 and BNIP3. The activation of apoptotic pathway in the cancer stem-like cells was suppressed by TOFA and by Fumonisin B1, suggesting that resveratrol-induced apoptosis is indeed through the modulation of FAS-mediated cell survival signaling. Importantly, resveratrol was able to significantly suppress the growth of cancer stem-like cells in an animal model of xenograft without showing apparental toxicity. Taken together, the results of this study indicate that resveratrol is capable of inducing apoptosis in the cancer stem-like cells through suppression of lipogenesis by modulating FAS expression, which highlights a novel mechanism of anti-tumor effect of resveratrol.

Keywords

Fatty acid synthase Lipogenesis Breast cancer Stem-like cells Apoptosis 

Abbreviations

FAS

Fatty acid synthase

ER+

Estrogen receptor positive

ER−

Estrogen receptor negative

DAPK2

Death associated kinase 2

BNIP3

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3

TRAIL

Tumor necrosis factor-related apoptosis-inducing ligand

ACC

Acetyl-CoA carboxylase

TOFA

5-(Tetradecyloxy)-2-furoic acid

qRT-PCR

Quantitative real-time PCR

Notes

Acknowledgments

This study was supported by the National Institutes of Health [R01CA124650 and R01CA129000], the Department of Defense, and Susan G. Komen Foundation.

References

  1. 1.
    Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506PubMedCrossRefGoogle Scholar
  2. 2.
    Pervaiz S (2003) Resveratrol: from grapevines to mammalian biology. FASEB J 17:1975–1985PubMedCrossRefGoogle Scholar
  3. 3.
    Aggarwal BB, Shishodia S (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71:1397–1421PubMedCrossRefGoogle Scholar
  4. 4.
    Levi F, Pasche C, Lucchini F, Ghidoni R, Ferraroni M, La Vecchia C (2005) Resveratrol and breast cancer risk. Eur J Cancer Prev 14:139–142PubMedCrossRefGoogle Scholar
  5. 5.
    Das S, Khan N, Mukherjee S et al (2008) Redox regulation of resveratrol-mediated switching of death signal into survival signal. Free Radic Biol Med 44:82–90PubMedCrossRefGoogle Scholar
  6. 6.
    Lin JK, Tsai SH (1999) Chemoprevention of cancer and cardiovascular disease by resveratrol. Proc Natl Sci Counc Repub China B 23:99–106PubMedGoogle Scholar
  7. 7.
    Renaud S, de Lorgeril M (1992) Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339:1523–1526PubMedCrossRefGoogle Scholar
  8. 8.
    Szkudelska K, Nogowski L, Szkudelski T (2009) Resveratrol, a naturally occurring diphenolic compound, affects lipogenesis, lipolysis and the antilipolytic action of insulin in isolated rat adipocytes. J Steroid Biochem Mol Biol 13:17–24CrossRefGoogle Scholar
  9. 9.
    Athar M, Back JH, Tang X, Kim KH, Kopelovich L, Bickers DR, Kim AL (2007) Resveratrol: a review of preclinical studies for human cancer prevention. Toxicol Appl Pharmacol 224:274–283PubMedCrossRefGoogle Scholar
  10. 10.
    Bishayee A (2009) Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev Res 2:409–418CrossRefGoogle Scholar
  11. 11.
    Jang M, Cai L, Udeani GO et al (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220PubMedCrossRefGoogle Scholar
  12. 12.
    Banerjee S, Bueso-Ramos C, Aggarwal BB (2002) Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res 62:4945–4954PubMedGoogle Scholar
  13. 13.
    Harper CE, Patel BB, Wang J, Arabshahi A, Eltoum IA, Lamartiniere CA (2007) Resveratrol suppresses prostate cancer progression in transgenic mice. Carcinogenesis 28:1946–1953PubMedCrossRefGoogle Scholar
  14. 14.
    Kuhajda FP (2000) Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 16:202–208PubMedCrossRefGoogle Scholar
  15. 15.
    Alo’ PL, Visca P, Marci A, Mangoni A, Botti C, Di Tondo U (1996) Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77:474–482PubMedCrossRefGoogle Scholar
  16. 16.
    Milgraum LZ, Witters LA, Pasternack GR, Kuhajda FP (1997) Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma. Clin Cancer Res 3:2115–2120PubMedGoogle Scholar
  17. 17.
    Rashid A, Pizer ES, Moga M et al (1997) Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. Am J Pathol 150:201–208PubMedGoogle Scholar
  18. 18.
    Swinnen JV, Roskams T, Joniau S et al (2002) Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer. Int J Cancer 98:19–22PubMedCrossRefGoogle Scholar
  19. 19.
    Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7:763–777PubMedCrossRefGoogle Scholar
  20. 20.
    Migita T, Ruiz S, Fornari A et al (2009) Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J Natl Cancer Inst 101:519–532PubMedCrossRefGoogle Scholar
  21. 21.
    Bandyopadhyay S, Zhan R, Wang Y et al (2006) Mechanism of apoptosis induced by the inhibition of fatty acid synthase in breast cancer cells. Cancer Res 66:5934–5940PubMedCrossRefGoogle Scholar
  22. 22.
    Liu H, Liu Y, Zhang JT (2008) A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction. Mol Cancer Ther 7:263–270PubMedCrossRefGoogle Scholar
  23. 23.
    Furuta E, Pai SK, Zhan R et al (2008) Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res 68:1003–1011PubMedCrossRefGoogle Scholar
  24. 24.
    Furuta E, Okuda H, Kobayashi A, Watabe K (2010) Metabolic genes in cancer: their roles in tumor progression and clinical implications. Biochim Biophys Acta 1805:141–152PubMedGoogle Scholar
  25. 25.
    Minn AJ, Gupta GP, Siegel PM et al (2005) Genes that mediate breast cancer metastasis to lung. Nature 436:518–524PubMedCrossRefGoogle Scholar
  26. 26.
    Al-Hajj M, Wicha MS, Benito-Hernandez A et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988PubMedCrossRefGoogle Scholar
  27. 27.
    Li C, Heidt DG, Dalerba P et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67(3):1030–1037PubMedCrossRefGoogle Scholar
  28. 28.
    Fillmore CM, Kuperwasser C (2008) Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 10(2):R2CrossRefGoogle Scholar
  29. 29.
    Li C, Lee CJ, Simeone DM (2009) Identification of human pancreatic cancer stem cells. Methods Mol Biol 568:161–173PubMedCrossRefGoogle Scholar
  30. 30.
    Huang TT, Lin HC, Chen CC et al (2010) Resveratrol induces apoptosis of human nasopharyngeal carcinoma cells via activation of multiple apoptotic pathways. J Cell Physiol [Epub ahead of print]Google Scholar
  31. 31.
    Vanamala J, Reddivari L, Radhakrishnan S, Tarver C (2010) Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways. BMC Cancer 10:238PubMedCrossRefGoogle Scholar
  32. 32.
    Lee MH, Choi BY, Kundu JK et al (2009) Resveratrol suppresses growth of human ovarian cancer cells in culture and in a murine xenograft model: eukaryotic elongation factor 1A2 as a potential target. Cancer Res 69(18):7449PubMedCrossRefGoogle Scholar
  33. 33.
    Boissy P, Andersen TL, Abdallah BM et al (2005) Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation. Cancer Res 65(21):9943–9952PubMedCrossRefGoogle Scholar
  34. 34.
    Jiang H, Shang X, Wu H et al (2009) Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. J Exp Ther Oncol 8(1):25–33PubMedGoogle Scholar
  35. 35.
    Hwang J-T, Kwon DY, Park OJ, Kim (2008) Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells. Genes Nutr 2(4):323–326. doi:10.1007/s12263-007-0069-7 PubMedCrossRefGoogle Scholar
  36. 36.
    Lin JN et al (2010) Resveratrol modulates tumor cell proliferation and protein translation via SIRT1-dependent AMPK activation. J Agric Food Chem 58(3):1584–1592PubMedCrossRefGoogle Scholar
  37. 37.
    Ahmad N, Adhami VM, Afaq F, Feyes DK, Mukhtar H (2001) Resveratrol causes WAF-1/p21-mediated G(1)-phase arrest of cell cycle and induction of apoptosis in human epidermoid carcinoma A431 cells. Clin Cancer Res 7:1466–1473PubMedGoogle Scholar
  38. 38.
    Bai Y, Mao QQ, Qin J et al (2010) Resveratrol induces apoptosis and cell cycle arrest of human T24 bladder cancer cells in vitro and inhibits tumor growth in vivo. Cancer Sci 101:488–493PubMedCrossRefGoogle Scholar
  39. 39.
    Gagliano N, Aldini G, Colombo G et al (2010) The potential of resveratrol against human gliomas. Anticancer Drugs 21:140–150PubMedCrossRefGoogle Scholar
  40. 40.
    Wang J, He D, Zhang Q, Han Y, Jin S, Qi F (2009) Resveratrol protects against Cisplatin-induced cardiotoxicity by alleviating oxidative damage. Cancer Biother Radiopharm 24:675–680PubMedCrossRefGoogle Scholar
  41. 41.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737PubMedCrossRefGoogle Scholar
  42. 42.
    Hope KJ, Jin L, Dick JE (2004) Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 5:738–743PubMedCrossRefGoogle Scholar
  43. 43.
    Marx J (2007) Molecular biology. Cancer’s perpetual source? Science 317:1029–1031PubMedCrossRefGoogle Scholar
  44. 44.
    Vitrac X, Desmoulière A, Brouillaud B et al (2003) Distribution of (14C)-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration. Life Sci 72:2219–2233PubMedCrossRefGoogle Scholar
  45. 45.
    Hamada J, Nakata D, Nakae D et al (2001) Increased oxidative DNA damage in mammary tumor cells by continuous epidermal growth factor stimulation. J Natl Cancer Inst 93:214–219PubMedCrossRefGoogle Scholar
  46. 46.
    Whyte L, Huang YY, Torres K, Mehta RG (2007) Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res 67:12007–12017PubMedCrossRefGoogle Scholar
  47. 47.
    Zhang J (2006) Resveratrol inhibits insulin responses in a SirT1-independent pathway. Biochem J 397:519–527PubMedCrossRefGoogle Scholar
  48. 48.
    Vazquez-Martin A, Colomer R, Brunet J, Lupu R, Menendez JA (2008) Overexpression of fatty acid synthase gene activates HER1/HER2 tyrosine kinase receptors in human breast epithelial cells. Cell Prolif 41:59–85PubMedCrossRefGoogle Scholar
  49. 49.
    Knowles LM, Yang C, Osterman A, Smith JW (2008) Inhibition of fatty-acid synthase induces caspase-8-mediated tumor cell apoptosis by up-regulating DDIT4. J Biol Chem 283:31378–31384PubMedCrossRefGoogle Scholar
  50. 50.
    Bandyopadhyay S, Pai SK, Watabe M et al (2005) FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis. Oncogene 24:5389–5395PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Puspa R. Pandey
    • 1
  • Hiroshi Okuda
    • 1
  • Misako Watabe
    • 1
  • Sudha K. Pai
    • 1
  • Wen Liu
    • 1
  • Aya Kobayashi
    • 1
  • Fei Xing
    • 1
  • Koji Fukuda
    • 1
  • Shigeru Hirota
    • 2
  • Tamotsu Sugai
    • 2
  • Go Wakabayashi
    • 2
  • Keisuke Koeda
    • 2
  • Masahiro Kashiwaba
    • 2
  • Kazuyuki Suzuki
    • 2
  • Toshimi Chiba
    • 2
  • Masaki Endo
    • 2
  • Tomoaki Fujioka
    • 2
  • Susumu Tanji
    • 2
  • Yin-Yuan Mo
    • 1
  • Deliang Cao
    • 1
  • Andrew C. Wilber
    • 3
  • Kounosuke Watabe
    • 1
  1. 1.Department of Medical Microbiology, Immunology & Cell BiologySouthern Illinois University School of MedicineSpringfieldUSA
  2. 2.Iwate Medical University, School of MedicineMoriokaJapan
  3. 3.Department of SurgerySouthern Illinois University School of MedicineSpringfieldUSA

Personalised recommendations