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 [1-11C]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 [1-11C]acetate PET.

Inhibition of FASN expression enhances radiosensitivity in human non-small cell lung cancer

“…Previous studies have demonstrated that the upregulation of FASN increases tumor cell proliferation (25), decreases the rate of apoptosis (17), and increases the resistance to chemotherapy and radiation of tumor cells in various human neoplasms (26). In line with this, the present study revealed that downregulation of FASN caused a significant reduction in the proliferation of A549 cells, suggesting that FASN may be involved in NSCLC oncogenesis.…”

The Fatty Acid Synthase Inhibitor Orlistat Reduces the Growth and Metastasis of Orthotopic Tongue Oral Squamous Cell Carcinomas

“…The biologic mechanisms that link FASN activity with metastatic spread are largely unknown and it is possible to speculate that the decreased number of metastatic lymph nodes here observed with orlistat is consequence of the cell growth/migration inhibition and enhanced apoptosis. It was also recently shown that the inhibition of lipogenesis reduces invadopodia formation and gelatinolytic activity of Src-transformed 3T3 cells (47) and that orlistat prevents pseudopodia formation and inhibits human prostate cancer cell migration and invasion (48). Kuemmerle and colleagues (49) recently demonstrated that in addition to de novo lipogenesis, cancer cells can use the lipoprotein lipase (LPL) and CD36 to acquire fatty acids from the circulation by lipolysis.…”

Evaluation of Prostate Cancer with 11C-Acetate PET/CT

“…Orlistat, a selective inhibitor of FAS, was tested for target inhibition in murine prostate cancer models. The degree of target expression as determined with 11 C-acetate imaging correlated with response to FAS inhibition (55).…”

“…Predictive biomarkers are designed to determine whether a specific therapeutic target is expressed (Fig. 5) (55). FAS is overexpressed in prostate and other cancers and has been explored as a potential therapeutic target.…”