The synthetic triterpenoid CDDO-Im inhibits fatty acid synthase expression and has antiproliferative and proapoptotic effects in human liposarcoma cells.
Liposarcomas constitute a rare group of tumors of mesenchymal origin that are often poorly responsive to therapy. This study characterizes a novel human liposarcoma cell line (LiSa-2) and defines the mechanism of its response to a synthetic triterpenoid. Fatty acid synthase (FAS) is a key enzyme of de-novo fatty acid synthesis and is highly expressed in both human liposarcoma tissue specimens and LiSa-2 cells. Treatment of the LiSa-2 cell line with the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic imidazolide (CDDO-Im) markedly inhibited FAS mRNA expression, FAS protein production and FAS gene promoter activity. As expected, fatty acid synthesis was down regulated, but there was no effect on cellular fatty acid uptake or glycerol-3-phosphate synthesis suggesting a selective inhibition of endogenous fatty acid synthesis. Importantly, CDDO-Im produced a dose-dependent apoptotic effect in the LiSa-2 cell line, and simultaneous treatment with CDDO-Im and the fatty acid synthase inhibitor Cerulenin produced a synergistic cytotoxic effect. Thus, CDDO-Im and Cerulenin act at different loci to inhibit long chain fatty acid synthesis in liposarcoma cells. This study's demonstration of CDDO-Im inhibition of FAS and Spot 14 (S14) expression is the first report of triterpenoid compounds affecting the fatty acid synthesis pathway. The observed dependence of liposarcomas on lipogenesis to support their growth and survival provides a novel approach to the treatment of liposarcomas with agents that target fatty acid production.
Hughes
David T
DT
Department of Surgery, Section of Surgical Oncology, Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA. David.T.Hughes@Hitchcock.org
Martel
Peter M
PM
Kinlaw
William B
WB
Eisenberg
Burton L
BL
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002569:Cerulenin / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D054872:Fatty Acid Synthesis Inhibitors / Q000494:pharmacology; D005993:Glycerolphosphate Dehydrogenase / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008080:Liposarcoma / Q000188:drug therapy*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D019308:Palmitic Acid / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; C491901:FAS protein, human; D054872:Fatty Acid Synthesis Inhibitors; D007093:Imidazoles; D019014:fas Receptor; D002569:Cerulenin; D019308:Palmitic Acid; D009828:Oleanolic Acid; D005993:Glycerolphosphate Dehydrogenase; D064429:Fatty Acid Synthases