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.
Highlights
Fatty acid synthase (FASN) is a key enzyme in fatty acid synthesis from acetyl CoA, which is expressed at high levels in liver and adipose tissue, but at low levels in other tissues in humans [1]
We have previously reported uptake mechanism of radiolabeled acetate into tumor cells; cytosolic acetyl-CoA synthetase, which converts acetate to acetylCoA, is over-expressed in tumor cells and plays a role in incorporation of radiolabeled acetate and the acetate incorporated into tumor cells is mainly used for fatty acid synthesis rather than breakdown to CO2 via tricarboxylic acid cycle or amino acid synthesis [7,8]
We examined whether radiolabeled acetate uptake can predict therapeutic outcome of FASN-targeted therapy using human prostate cancer cell lines to demonstrate applicability of [1-11C]acetate positron emission tomography (PET) as a predictor of FASN-targeted therapy outcome
Summary
Fatty acid synthase (FASN) is a key enzyme in fatty acid synthesis from acetyl CoA, which is expressed at high levels in liver and adipose tissue, but at low levels in other tissues in humans [1]. FASN has been demonstrated to play an important role in carcinogenesis by protecting cells from apoptosis [2]. Inhibitors of FASN reportedly show antitumor activity [4]. Orlistat is reported to exert antitumor activity by inducing apoptosis in tumor cells [3,5]. FASN-targeted therapy is expected to be effective against FASN-expressing tumors. Large variations in FASN expression levels in individual tumors have been observed by pathological studies [2,6]. When considering application of FASN-targeted therapy, methods to predict therapeutic outcome in individual tumors before treatment are needed to reduce unnecessary treatment
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