Fatty acid synthase inhibition results in a magnetic resonance-detectable drop in phosphocholine.
Expression of fatty acid synthase (FASN), the key enzyme in de novo synthesis of long-chain fatty acids, is normally low but increases in cancer. Consequently, FASN is a novel target for cancer therapy. However, because FASN inhibitors can lead to tumor stasis rather than shrinkage, noninvasive methods for assessing FASN inhibition are needed. To this end, we combined (1)H, (31)P, and (13)C magnetic resonance spectroscopy (MRS) (a) to monitor the metabolic consequences of FASN inhibition and (b) to identify MRS-detectable metabolic biomarkers of response. Treatment of PC-3 cells with the FASN inhibitor Orlistat for up to 48 h resulted in inhibition of FASN activity by 70%, correlating with 74% inhibition of fatty acid synthesis. Furthermore, we have determined that FASN inhibition results not only in lower phosphatidylcholine levels but also in a 59% drop in the phospholipid precursor phosphocholine (PCho). This drop resulted from inhibition in PCho synthesis as a result of a reduction in the cellular activity of its synthetic enzyme choline kinase. The drop in PCho levels following FASN inhibition was confirmed in SKOV-3 ovarian cancer cells treated with Orlistat and in MCF-7 breast cancer cells treated with Orlistat as well as cerulenin. Combining data from all treated cells, the drop in PCho significantly correlated with the drop in de novo synthesized fatty acid levels, identifying PCho as a potential noninvasive MRS-detectable biomarker of FASN inhibition in vivo.
Ross
James
J
Department of Radiology, University of California-San Francisco, 1700 4th Street, San Francisco, CA 94158, USA.
Najjar
Amer M
AM
Sankaranarayanapillai
Madhuri
M
Tong
William P
WP
Kaluarachchi
Kumaralal
K
Ronen
Sabrina M
SM
D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D000077403:Orlistat; D010767:Phosphorylcholine / Q000378:metabolism*
D017931:DNA Primers; D004791:Enzyme Inhibitors; D007783:Lactones; D010767:Phosphorylcholine; D000077403:Orlistat; D064429:Fatty Acid Synthases