Pharmacological inhibitor of fatty acid synthase suppresses growth and invasiveness of renal cancer cells.
OBJECTIVE
Fatty acid synthase has been shown to be over expressed in a wide range of cancers and it has emerged as a therapeutic target. We examined whether fatty acid synthase could be a novel therapeutic target for renal cell carcinoma using the pharmacological fatty acid synthase inhibitor C75 (Cayman Chemical, Ann Arbor, Michigan).


METHODS
The effects of C75 on cell viability and proliferation in human renal cancer 769P (ATCC(R)), Caki-1 and KU20-01 cells were examined by MTS assay and cell counts. Cell cycle distribution was analyzed by flow cytometry and cell invasiveness was assessed by wound healing and Matrigel(trade mark) invasion assays. Fatty acid synthase expression and the effects of C75 on intracellular signaling pathways were analyzed by Western blotting. The antitumor efficacy of C75 was examined using Caki-1 cell xenografts.


RESULTS
All renal cancer cell lines expressed detectable fatty acid synthase. C75 (10 mug/ml) significantly inhibited cell viability and growth by arresting the cell cycle at the G2/M phase and inducing apoptosis (p <0.01). The covered area in the wound and the number of cells invading through a Matrigel chamber were significantly smaller for cells treated with C75 than they were for control cells treated with vehicle (p <0.001). C75 suppressed Her2 and epidermal growth factor receptor expression as well as STAT3 phosphorylation, while increasing p53 and p21(Waf1/Cip1) expression. Intraperitoneal administration of C75 at doses of 20 mg/kg per week for 28 days significantly reduced the tumor volume of Caki-1 xenografts (p <0.05).


CONCLUSIONS
Pharmacological inhibition of fatty acid synthase could be an effective strategy for treating renal cell carcinoma.
Department of Urology, National Defense Medical College, Tokorozawa-City, Saitama, Japan.
Akio
A
Horiguchi
Tomohiko
T
Asano
Takako
T
Asano
Keiichi
K
Ito
Makoto
M
Sumitomo
Masamichi
M
Hayakawa
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000473:pathology; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004195:Disease Models, Animal; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D007274:Injections, Intraperitoneal; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D011336:Probability; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D064429:Fatty Acid Synthases; D004121:Dimethyl Sulfoxide