Fatty acid synthase: a novel target for antiglioma therapy.
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.
Zhao
W
W
Department of Radiation Oncology, Brain Tumor Center of Excellence, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. wzhao@wfubmc.edu
Kridel
S
S
Thorburn
A
A
Kooshki
M
M
Little
J
J
Hebbar
S
S
Robbins
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects; D001483:Base Sequence; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D002569:Cerulenin / Q000494:pharmacology; D024161:Collagen Type XI / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering; D011836:Radiation Tolerance / Q000187:drug effects; D051381:Rats; D014162:Transfection
C499319:COL11A2 protein, human; D024161:Collagen Type XI; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D002569:Cerulenin; D064429:Fatty Acid Synthases