Fatty acid synthase inhibitor cerulenin suppresses liver metastasis of colon cancer in mice

Abstract

Fatty acid synthase (FAS) is highly expressed in many kinds of human cancers, including colorectal cancer (CRC), and we have investigated the potential use of FAS inhibitors for chemoprevention of liver metastasis of CRC in mice. Expression of FAS was evaluated in murine CRC cell lines Colon 26 and CMT 93. Cerulenin, a natural inhibitor of FAS, induced apoptosis in these cell lines. The ability of cerulenin to prevent development of liver metastatic lesions in Colon 26 was evaluated. The numbers and sizes of liver metastatic CRC tumors were significantly reduced by treating mice with cerulenin. Cerulenin treatment was associated with reduced levels of phosphorylated Akt in Colon 26 cells, suggesting that inhibition of this signal transduction pathway might be involved in the chemopreventive activity of this compound. Based on studies in mouse models, inhibiting FAS would be an effective strategy to prevent and retard growth of liver metastatic tumors of CRC that have high expression of this enzyme. (Cancer Sci 2010; 101: 1861-1865 C olorectal cancer (CRC) is one of the most common cancers in the world with more than 1 million new cases.(1) The liver is the commonest site of distant metastasis in CRC, and approximately 50% of patients ultimately develop liver metastasis in the course of CRC.(1,2) Despite recent advances, systemic chemotherapy for metastatic disease is considered palliative, and we rarely see long-term survivors treated only by chemotherapy.(1) Hepatic resection, the only curative treatment for liver metastasis of CRC, has become the standard treatment, but most cases of liver metastases are inoperable and approximately 50% of the patients treated with hepatectomy have a tumor recurrence in the liver. Fatty acid synthase (FAS) is highly expressed in many human cancers including CRC, (4)(5)(6)(7) and previous studies have shown that cancer cell growth can be suppressed by inhibiting the activity of this enzyme with a natural antibiotic cerulenin, (8) orlistat, which is a pancreatic lipase inhibitor developed for obesity treatment, (9) and C75, which is a stable synthetic small molecule developed specifically for inhibiting FAS.(10) But there are no previous studies in which FAS inhibitors suppressed liver metastasis of CRC.The aim of this study extends the investigation of the potential use of an FAS inhibitor for the chemoprevention of liver metastasis of CRC in mice. In this study, we examined the effect of cerulenin on cell proliferation and apoptosis in murine CRC cell lines Colon 26 and CMT 93. Then, the effect of cerulenin on the prevention of growth of liver metastasis lesions in Colon 26 was investigated. Materials and MethodsCerulenin. Cerulenin was obtained from Sigma (St. Louis, MO, USA). For cell culture and i.p. injections, cerulenin was dissolved in acetone at a concentration of 20 mg ⁄ mL and stored at )20°C. In in vitro experiment, 50-200 lM of cerulenin was added to the medium, and cell viability assay and western blot experiments were performed 24 h later. In in vivo experiments,...

Fatty acid synthase expression in osteosarcoma and its correlation with pulmonary metastasis

“…The difference in FASN expression level between OS and osteoenchondroma was significant (p<0.01). Recent studies have shown that FASN expression levels are associated with tumor cells metastasis in vivo (20,30). In our study, FASN was overexpressed in 38 of 44 patients with pulmonary metastasis, but only 48 of the 92 patients without metastasis demonstrated positive FASN expression.…”

“…Recent studies revealed that the inhibition of FASN promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model (19). In Colon 26 and CMT 93 cells, FASN contributed to metastasis by upregulating the activity of the AKT pathway (20). However, the expression of FASN and the correlation between FASN and metastasis in OS is still uncertain.…”

G Protein-coupled Estrogen Receptor Mediates the Up-regulation of Fatty Acid Synthase Induced by 17β-Estradiol in Cancer Cells and Cancer-associated Fibroblasts

“…, which was previously shown to repress cancer cell growth by inhibiting fatty acid synthesis (37)(38)(39)(40)(41)(42)(43). Proliferation assays were also performed using cerulenin in cells transfected with an expression vector of FASN (Fig.…”

microRNA-195 suppresses osteosarcoma cell invasion and migration in vitro by targeting FASN

“…Thus, FASN is considered a novel promising target for anticancer therapy. Recent studies (21,22) have revealed that FASN may also contribute to cancer cell metastasis. microRNAs (miRNAs) are endogenous small RNAs averaging 20 to 24 nucleotides, transcribed from non-protein-coding genes or introns, which mediate translational suppression or cleavage of their target mRNAs by binding to complementary sites in their 3'-UTR (23)(24)(25).…”