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Fatty acid synthase is a metabolic marker of cell proliferation rather than malignancy in ovarian cancer and its precursor cells
Author(s) -
Veigel Daniel,
Wagner Renate,
Stübiger Gerald,
Wuczkowski Michael,
Filipits Martin,
Horvat Reinhard,
Benhamú Bellinda,
LópezRodríguez María Luz,
Leisser Asha,
Valent Peter,
Grusch Michael,
Hegardt Fausto G.,
García Jordi,
Serra Dolors,
Auersperg Nelly,
Colomer Ramón,
Grunt Thomas W.
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29261
Subject(s) - fatty acid synthase , biology , cell growth , apoptosis , cancer cell , cancer research , senescence , ovarian cancer , cancer , microbiology and biotechnology , endocrinology , lipid metabolism , biochemistry , genetics
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.