title: Fatty acid synthase is a key target in multiple essential tumor functions of prostate cancer: uptake of radiolabeled acetate as a predictor of the targeted therapy outcome.
abstract: Fatty acid synthase (FASN) expression is elevated in several cancers, and this over-expression is associated with poor prognosis. Inhibitors of FASN, such as orlistat, reportedly show antitumor effects against cancers that over-express FASN, making FASN a promising therapeutic target. However, large variations in FASN expression levels in individual tumors have been observed, and methods to predict FASN-targeted therapy outcome before treatment are required to avoid unnecessary treatment. In addition, how FASN inhibition affects tumor progression remains unclear. Here, we showed the method to predict FASN-targeted therapy outcome using radiolabeled acetate uptake and presented mechanisms of FASN inhibition with human prostate cancer cell lines, to provide the treatment strategy of FASN-targeted therapy. We revealed that tumor uptake of radiolabeled acetate reflected the FASN expression levels and sensitivity to FASN-targeted therapy with orlistat in vitro and in vivo. FASN-targeted therapy was noticeably effective against tumors with high FASN expression, which was indicated by high acetate uptake. To examine mechanisms, we established FASN knockdown prostate cancer cells by transduction of short-hairpin RNA against FASN and investigated the characteristics by analyses on morphology and cell behavior and microarray-based gene expression profiling. FASN inhibition not only suppressed cell proliferation but prevented pseudopodia formation and suppressed cell adhesion, migration, and invasion. FASN inhibition also suppressed genes involved in production of intracellular second messenger arachidonic acid and androgen hormones, both of which promote tumor progression. Collectively, our data demonstrated that uptake of radiolabeled acetate is a useful predictor of FASN-targeted therapy outcome. This suggests that [1-(11)C]acetate positron emission tomography (PET) could be a powerful tool to accomplish personalized FASN-targeted therapy by non-invasive visualization of tumor acetate uptake and selection of responsive tumors. FASN-targeted therapy could be an effective treatment to suppress multiple steps related to tumor progression in prostate cancers selected by [1-(11)C]acetate PET.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan. yukiey@nirs.go.jp
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yoshii
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Oyama
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kiyono
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishii
authors.forename: Atsuo
authors.initials: A
authors.lastname: Waki
authors.forename: Atsushi B
authors.initials: AB
authors.lastname: Tsuji
authors.forename: Chizuru
authors.initials: C
authors.lastname: Sogawa
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Wakizaka
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Fukumura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshii
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D019342:Acetic Acid; D000230:Adenocarcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport; D002250:Carbon Radioisotopes; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D058990:Molecular Targeted Therapy; D009374:Neoplasms, Experimental; D000077403:Orlistat; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D007783:Lactones; D034741:RNA, Small Interfering; D000077403:Orlistat; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D019342:Acetic Acid