Cancer Cell Biology

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Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model

  1. Marco A. Carvalho1,
  2. Karina G. Zecchin2,
  3. Fabiana Seguin1,
  4. Débora C. Bastos1,
  5. Michelle Agostini1,
  6. Ana Lúcia C.A. Rangel1,
  7. Sílvio S. Veiga3,
  8. Helena F. Raposo4,
  9. Helena C.F. Oliveira4,
  10. Massimo Loda5,
  11. Ricardo D. Coletta1,
  12. Edgard Graner1,†,*

Article first published online: 3 SEP 2008

DOI: 10.1002/ijc.23835

Issue

International Journal of Cancer

International Journal of Cancer

Volume 123, Issue 11, pages 2557–2565, 1 December 2008

Additional Information

How to Cite

Carvalho, M. A., Zecchin, K. G., Seguin, F., Bastos, D. C., Agostini, M., Rangel, A. L. C., Veiga, S. S., Raposo, H. F., Oliveira, H. C., Loda, M., Coletta, R. D. and Graner, E. (2008), Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model. International Journal of Cancer, 123: 2557–2565. doi: 10.1002/ijc.23835

Author Information

  1. 1

    Department of Oral Diagnosis, School of Dentistry of Piracicaba, State University of Campinas (UNICAMP), Piracicaba, Sao Paulo, Brazil

  2. 2

    Department of Clinical Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil

  3. 3

    Department of Cell Biology, Federal University of Paraná, Brazil

  4. 4

    Department of Physiology and Biophysics, Institute of Biology, State University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil

  5. 5

    Medical Oncology, Dana-Farber Cancer Institute and Pathology Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

  1. †

    Fax: 55-19-2106-5318.

*Department of Oral Diagnosis, School of Dentistry of Piracicaba, State University of Campinas (UNICAMP), Avenida Limeira 901, CP 52, Areão, Piracicaba, Sao Paulo, 13414-018, Brazil

Publication History

  1. Issue published online: 24 SEP 2008
  2. Article first published online: 3 SEP 2008
  3. Manuscript Accepted: 20 JUN 2008
  4. Manuscript Received: 9 NOV 2007

Funded by

  • Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). Grant Numbers: 04/13903-0, 02/08030-1
  • FAPESP fellowships. Grant Numbers: 05/52631-8, 05/50297-3, 04/13904-6, 04/06397-0
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico fellowships. Grant Numbers: PIBIC-CNPq, 151125/2005-8

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Keywords:

  • melanoma;
  • fatty acid synthase;
  • metastasis;
  • Orlistat;
  • B16-F10 cells

Abstract

Fatty acid synthase (FASN) is the enzyme responsible for the endogenous synthesis of the saturated fatty acid palmitate. In contrast to most normal cells, malignant cells depend on FASN activity for growth and survival. In fact, FASN is overexpressed in a variety of human cancers including cutaneous melanoma, in which its levels of expression are associated with a poor prognosis and depth of invasion. Here, we show that the specific inhibition of FASN activity by the antiobesity drug Orlistat or siRNA is able to significantly reduce proliferation and promote apoptosis in the mouse metastatic melanoma cell line B16-F10. These results prompted us to verify the effect of FASN inhibition on the metastatic process in a model of spontaneous melanoma metastasis, in which B16-F10 cells injected in the peritoneal cavity of C57BL/6 mice metastasize to the mediastinal lymph nodes. We observed that mice treated with Orlistat 48 hr after the inoculation of B16-F10 cells exhibited a 52% reduction in the number of mediastinal lymph node metastases, in comparison with the control animals. These results suggest that FASN activity is essential for B16-F10 melanoma cell proliferation and survival while its inactivation by Orlistat significantly reduces their metastatic spread. The chemical inhibition of FASN activity could have a potential benefit in association with the current chemotherapy for melanoma. © 2008 Wiley-Liss, Inc.

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