title: Trophoblastic neoplasms express fatty acid synthase, which may be a therapeutic target via its inhibitor C93.
abstract: Fatty acid synthase (FASN) is an emerging tumor-associated marker and a promising antitumor therapeutic target. In this study, we analyzed the expression of FASN in normal and molar placentas, as well as gestational trophoblastic neoplasia, and assessed the effects of a new FASN inhibitor, C93, on cellular proliferation and apoptosis in choriocarcinoma cells. Using a FASN-specific monoclonal antibody, we found that FASN immunoreactivity was detected in the cytotrophoblast and intermediate (extravillous) trophoblast of normal and molar placentas, as well as in placental site nodules. All choriocarcinomas (n = 33), 90% of epithelioid trophoblastic tumors (n = 20), and 60% of placental site trophoblastic tumors (n = 10) exhibited FASN positivity. FASN expression was further confirmed in vitro by Western blot and real-time PCR. Treatment of JEG3 and JAR cells with C93 induced significant apoptosis through the caspase-3/caspase-9/poly(ADP)ribose polymerase pathway. Cell cycle progression was not affected by the inhibitor. In summary, the data indicate that FASN is expressed in the majority of gestational trophoblastic neoplasias, and is essential for choriocarcinoma cells to survive and escape from apoptosis. FASN inhibitors such as C93 warrant further investigation as targeted therapeutic agents for metastatic and chemoresistant gestational trophoblastic neoplasia.
authors.affiliation: Kelly Gynecologic Oncology Service, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Ueda
authors.forename: Tsui-Lien
authors.initials: TL
authors.lastname: Mao
authors.forename: Francis P
authors.initials: FP
authors.lastname: Kuhajda
authors.forename: Chanont
authors.initials: C
authors.lastname: Vasoontara
authors.forename: Robert L
authors.initials: RL
authors.lastname: Giuntoli
authors.forename: Robert E
authors.initials: RE
authors.lastname: Bristow
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kurman
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006828:Hydatidiform Mole / Q000201:enzymology; D007150:Immunohistochemistry; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014328:Trophoblastic Neoplasms / Q000201:enzymology*; D014594:Uterine Neoplasms / Q000201:enzymology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D064429:Fatty Acid Synthases