Fatty acid synthase is a metabolic marker of cell proliferation rather than malignancy in ovarian cancer and its precursor cells
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
Search for more papers by this authorRenate 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
Search for more papers by this authorGerald 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
Search for more papers by this authorMichael Wuczkowski
Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University Vienna, Vienna, Austria
Search for more papers by this authorMartin Filipits
Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
Search for more papers by this authorReinhard Horvat
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
Search for more papers by this authorBellinda Benhamú
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain
Search for more papers by this authorMaría Luz López-Rodríguez
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain
Search for more papers by this authorAsha Leisser
Signaling Networks Program, Division of Oncology, Department of Medicine I, Medical University Vienna, Vienna, Austria
Ludwig Boltzmann Cluster Oncology, Vienna, Austria
Search for more papers by this authorPeter 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
Search for more papers by this authorMichael Grusch
Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
Search for more papers by this authorFausto 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
Search for more papers by this authorJordi 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
Search for more papers by this authorDolors 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
Search for more papers by this authorNelly Auersperg
Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
Search for more papers by this authorRamón Colomer
Department of Medical Oncology, Hospital Universitario La Princesa, Madrid, Spain
Clinical Research Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain
Search for more papers by this authorCorresponding 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 authorDaniel 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
Search for more papers by this authorRenate 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
Search for more papers by this authorGerald 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
Search for more papers by this authorMichael Wuczkowski
Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University Vienna, Vienna, Austria
Search for more papers by this authorMartin Filipits
Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
Search for more papers by this authorReinhard Horvat
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
Search for more papers by this authorBellinda Benhamú
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain
Search for more papers by this authorMaría Luz López-Rodríguez
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain
Search for more papers by this authorAsha Leisser
Signaling Networks Program, Division of Oncology, Department of Medicine I, Medical University Vienna, Vienna, Austria
Ludwig Boltzmann Cluster Oncology, Vienna, Austria
Search for more papers by this authorPeter 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
Search for more papers by this authorMichael Grusch
Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
Search for more papers by this authorFausto 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
Search for more papers by this authorJordi 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
Search for more papers by this authorDolors 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
Search for more papers by this authorNelly Auersperg
Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
Search for more papers by this authorRamón Colomer
Department of Medical Oncology, Hospital Universitario La Princesa, Madrid, Spain
Clinical Research Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain
Search for more papers by this authorCorresponding 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 authorConflict 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.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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| ijc29261-sup-0003-suppfig2.pdf117.4 KB |
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| ijc29261-sup-0004-suppfig3.pdf209.7 KB |
Supporting Information Figure 3 |
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