Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells.
Development and progression of cancer is accompanied by marked changes in the expression and activity of enzymes involved in the cellular homeostasis of fatty acids. One class of enzymes that play a particularly important role in this process are the acetyl-CoA carboxylases (ACC). ACCs produce malonyl-CoA, an intermediate metabolite that functions as substrate for fatty acid synthesis and as negative regulator of fatty acid oxidation. Here, using the potent ACC inhibitor soraphen A, a macrocyclic polyketide from myxobacteria, we show that ACC activity in cancer cells is essential for proliferation and survival. Even at nanomolar concentrations, soraphen A can block fatty acid synthesis and stimulate fatty acid oxidation in LNCaP and PC-3M prostate cancer cells. As a result, the phospholipid content of cancer cells decreased, and cells stopped proliferating and ultimately died. LNCaP cells predominantly died through apoptosis, whereas PC-3M cells showed signs of autophagy. Supplementation of the culture medium with exogenous palmitic acid completely abolished the effects of soraphen A and rescued the cells from cell death. Interestingly, when added to cultures of premalignant BPH-1 cells, soraphen A only slightly affected cell proliferation and did not induce cell death. Together, these findings indicate that cancer cells have become dependent on ACC activity to provide the cell with a sufficient supply of fatty acids to permit proliferation and survival, introducing the concept of using small-molecule ACC inhibitors as therapeutic agents for cancer.
Beckers
Annelies
A
Laboratory for Experimental Medicine and Endocrinology, Gasthuisberg, KU Leuven, Leuven, Belgium.
Organe
Sophie
S
Timmermans
Leen
L
Scheys
Katryn
K
Peeters
Annelies
A
Brusselmans
Koen
K
Verhoeven
Guido
G
Swinnen
Johannes V
JV
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D008297:Male; D009369:Neoplasms / Q000473:pathology*; D019308:Palmitic Acid / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured