Volume 136, Issue 9 pp. 2078-2090
Cancer Cell Biology

Fatty acid synthase is a metabolic marker of cell proliferation rather than malignancy in ovarian cancer and its precursor cells

Daniel Veigel

Daniel Veigel

Signaling Networks Program, Division of Oncology, Department of Medicine I, Medical University Vienna, Vienna, Austria

Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria

D.V. and R.W. contributed equally to this work

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Renate Wagner

Renate Wagner

Signaling Networks Program, Division of Oncology, Department of Medicine I, Medical University Vienna, Vienna, Austria

Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria

D.V. and R.W. contributed equally to this work

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Gerald Stübiger

Gerald Stübiger

Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria

Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University Vienna, Vienna, Austria

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Michael Wuczkowski

Michael Wuczkowski

Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University Vienna, Vienna, Austria

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Martin Filipits

Martin Filipits

Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria

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Reinhard Horvat

Reinhard Horvat

Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria

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Bellinda Benhamú

Bellinda Benhamú

Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain

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María Luz López-Rodríguez

María Luz López-Rodríguez

Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain

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Asha Leisser

Asha Leisser

Signaling Networks Program, Division of Oncology, Department of Medicine I, Medical University Vienna, Vienna, Austria

Ludwig Boltzmann Cluster Oncology, Vienna, Austria

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Peter Valent

Peter Valent

Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria

Ludwig Boltzmann Cluster Oncology, Vienna, Austria

Division of Hematology and Hemostaseology, Department of Medicine I, Medical University Vienna, Vienna, Austria

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Michael Grusch

Michael Grusch

Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria

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Fausto G. Hegardt

Fausto G. Hegardt

Department of Biochemistry and Molecular Biology, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain

Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain

CIBERobn Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain

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Jordi García

Jordi García

Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain

CIBERobn Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain

Department of Organic Chemistry, Facultat de Química, Universitat de Barcelona, Barcelona, Spain

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Dolors Serra

Dolors Serra

Department of Biochemistry and Molecular Biology, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain

Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain

CIBERobn Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain

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Nelly Auersperg

Nelly Auersperg

Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada

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Ramón Colomer

Ramón Colomer

Department of Medical Oncology, Hospital Universitario La Princesa, Madrid, Spain

Clinical Research Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

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Thomas W. Grunt

Corresponding Author

Thomas W. Grunt

Signaling Networks Program, Division of Oncology, Department of Medicine I, Medical University Vienna, Vienna, Austria

Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria

Ludwig Boltzmann Cluster Oncology, Vienna, Austria

Correspondence to: Thomas W. Grunt, Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria, Tel.: +43-1-40400-54570, −44300, Fax: +43-1-40400-54650, E-mail: [email protected]Search for more papers by this author
First published: 10 October 2014
Citations: 58

Conflict of interest: Nothing to report

Abstract

Ovarian cancer (OC) is caused by genetic aberrations in networks that control growth and survival. Importantly, aberrant cancer metabolism interacts with oncogenic signaling providing additional drug targets. Tumors overexpress the lipogenic enzyme fatty acid synthase (FASN) and are inhibited by FASN blockers, whereas normal cells are FASN-negative and FASN-inhibitor-resistant. Here, we demonstrate that this holds true when ovarian/oviductal cells reside in their autochthonous tissues, whereas in culture they express FASN and are FASN-inhibitor-sensitive. Upon subculture, nonmalignant cells cease growth, express senescence-associated β-galactosidase, lose FASN and become FASN-inhibitor-resistant. Immortalized ovarian/oviductal epithelial cell lines—although resisting senescence—reveal distinct growth activities, which correlate with FASN levels and FASN drug sensitivities. Accordingly, ectopic FASN stimulates growth in these cells. Moreover, FASN levels and lipogenic activities affect cellular lipid composition as demonstrated by thin-layer chromatography. Correlation between proliferation and FASN levels was finally evaluated in cancer cells such as HOC-7, which contain subclones with variable differentiation/senescence and corresponding FASN expression/FASN drug sensitivity. Interestingly, senescent phenotypes can be induced in parental HOC-7 by differentiating agents. In OC cells, FASN drugs induce cell cycle blockade in S and/or G2/M and stimulate apoptosis, whereas in normal cells they only cause cell cycle deceleration without apoptosis. Thus, normal cells, although growth-inhibited, may survive and recover from FASN blockade, whereas malignant cells get extinguished. FASN expression and FASN drug sensitivity are directly linked to cell growth and correlate with transformation/differentiation/senescence only indirectly. FASN is therefore a metabolic marker of cell proliferation rather than a marker of malignancy and is a useful target for future drug development.

Abstract

What's new?

Fatty acid synthase (FASN)—which is overexpressed in cancer and regulates oncogenic de-novo-lipogenesis—has been regarded as a marker of malignancy. Contrarily to the widely accepted concept that normal cells are negative for FASN, here the authors demonstrate that FASN is overexpressed in the ovarian system when cells reveal high growth rates, irrespective of their state of malignancy/differentiation/senescence. FASN thus represents a metabolic marker of ovarian cell proliferation rather than cancer. The study further shows that FASN is a useful cancer target, since quiescent normal cells usually lack it and the few positive dividing normal cells are spared by FASN-drugs.

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