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Fatty acid synthase inhibition results in a magnetic resonance-detectable drop in phosphocholine
James Ross1, Amer M Najjar, Madhuri Sankaranarayanapillai
1Department of Radiology, University of California-San Francisco, 1700 4th Street, San Francisco, CA 94158, USA.
Abstract:
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.
Insights
Fatty acid synthase (FASN) inhibition in cancer cells reduces fatty acid synthesis. Phosphocholine (PCho) levels drop significantly, serving as a potential noninvasive biomarker for FASN inhibition in cancer therapy.
Area of Science:
- Biochemistry
- Oncology
- Medical Imaging
Background:
- Fatty acid synthase (FASN) is crucial for synthesizing fatty acids and is upregulated in various cancers.
- FASN is a promising therapeutic target in oncology.
- Assessing FASN inhibition noninvasively is critical, as inhibitors may cause tumor stasis rather than shrinkage.
Purpose of the Study:
- To monitor metabolic changes resulting from FASN inhibition using magnetic resonance spectroscopy (MRS).
- To identify MRS-detectable metabolic biomarkers indicative of FASN inhibitor response.
- To validate phosphocholine (PCho) as a potential biomarker for FASN inhibition.
Main Methods:
- Utilized proton ((1)H), phosphorus ((31)P), and carbon ((13)C) MRS to analyze metabolic consequences of FASN inhibition.
- Treated cancer cell lines (PC-3, SKOV-3, MCF-7) with FASN inhibitors (Orlistat, cerulenin).
- Quantified FASN activity, fatty acid synthesis, and metabolite levels, including PCho.
Main Results:
- Orlistat treatment inhibited FASN activity by 70% and fatty acid synthesis by 74% in PC-3 cells.
- FASN inhibition led to decreased phosphatidylcholine and a 59% drop in phosphocholine (PCho) levels.
- The reduction in PCho levels correlated significantly with decreased de novo fatty acid synthesis across multiple cell lines and inhibitors.
Conclusions:
- Phosphocholine (PCho) is a reliable, MRS-detectable biomarker for assessing FASN inhibition in cancer cells.
- This finding supports the development of noninvasive methods to monitor therapeutic response to FASN inhibitors.
- PCho levels can serve as an indicator of FASN pathway activity in vivo.
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