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.