Fatty acid synthase inhibition results in a magnetic resonance-detectable drop in phosphocholine.
Fatty acid synthase inhibition results in a magnetic resonance-detectable drop in phosphocholine.
复制标题
脂肪酸合酶抑制导致磁共振可检测到的磷酸胆碱下降。
DOI：
10.1158/1535-7163.mct-08-0015
复制
发表时间：
2008-08
影响因子：
5.7
通讯作者：
Ronen SM
中科院分区：
文献类型：
--
作者：
Ross J;Najjar AM;Sankaranarayanapillai M;Tong WP;Kaluarachchi K;Ronen SM
Expression of fatty acid synthase (FASN), the key enzyme in de novo synthesis of long-chain fatty acids (FA), 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, non-invasive methods for assessing FASN inhibition are needed. To this end, we combined 1H, 31P and 13C magnetic resonance spectroscopy (MRS) (i) to monitor the metabolic consequences of FASN inhibition and (ii) 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 FA 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 FA levels, identifying PCho as a potential non-invasive MRS-detectable biomarker of FASN inhibition in vivo.
