Fatty acid synthase: a novel target for antiglioma therapy

Abstract

High levels of fatty acid synthase (FAS) expression have been observed in several cancers, including breast, prostate, colon and lung carcinoma, compared with their respective normal tissue. We present data that show high levels of FAS protein in human and rat glioma cell lines and human glioma tissue samples, as compared to normal rat astrocytes and normal human brain. Incubating glioma cells with the FAS inhibitor cerulenin decreased endogenous fatty acid synthesis by approximately 50%. Cell cycle analysis demonstrated a time-and dose-dependent increase in S-phase cell arrest following cerulenin treatment for 24 h. Further, treatment with cerulenin resulted in time-and dose-dependent decreases in glioma cell viability, as well as reduced clonogenic survival. Increased apoptotic cell death and PARP cleavage were observed in U251 and SNB-19 cells treated with cerulenin, which was independent of the death receptor pathway. Overexpressing Bcl-2 inhibited cerulenin-mediated cell death. In contrast, primary rat astrocytes appeared unaffected. Finally, RNAi-mediated knockdown of FAS leading to reduced FAS enzymatic activity was associated with decreased glioma cell viability. These findings suggest that FAS might be a novel target for antiglioma therapy.

Tumor cell metabolism

“…80 The siRNA-mediated silencing of FASN or the use of FASN inhibitors, such as cerulenin, C75 and orlistat, has been shown to induce apoptosis in several cancer lines. 80,87,88 Unlike previously studied drugs, FASN inhibition with C93 significantly inhibited growth without causing anorexia or weight loss in the treated animals; hence, it has promising therapeutic potential. 89 Tumor cells also express high levels of the lipogenic enzymes ACLY and ACC, consistent with the necessity of robust lipid synthesis.…”

“…In contrast, several human cancers, including lung, prostate, ovary, breast, endometrium and colon have often shown FASN overexpression. [78][79][80][81][82][83][84][85][86][87] This overexpression has been shown to participate in very early tumorigenesis, tumor growth and survival. 76,86 FASN upregulation also protects cells from death by inhibiting the intrinsic pathway of apoptosis.…”

Inhibition of Fatty Acid Synthase Sensitizes Prostate Cancer Cells to Radiotherapy

“…Inhibition of FASN, either pharmacologically or by siRNA, has previously been demonstrated to decrease viability, proliferation and clonogenic survival and increase apoptosis of cancer cells, but not nonmalignant cells (7,(12)(13)(14). Moreover, FASN inhibition reduced the growth rate of prostate cancer in experimental animals (15).…”

Novel Inhibitors of Fatty Acid Synthase with Anticancer Activity

“…1). Cerulenin, a natural antibiotic product of the fungus Cephalosporium ceruleans (8), inhibits FASN activity leading to apoptotic cancer cell death in vitro (9,10). C75, a synthetic analogue of cerulenin, is also a potent FASN inhibitor (11), which is cytotoxic for various tumor cell lines in vitro (12,13), and shows significant in vivo antitumor activity against human cancer cell xenografts (14,15).…”