Most tumors have an aberrantly activated lipid metabolism
1
,
2
,
which enables them to synthesize, elongate and desaturate fatty acids to support
proliferation. However, only particular subsets of cancer cells are sensitive
toward approaches targeting fatty acid metabolism, and in particular fatty acid
desaturation
3
. This suggests that many
cancer cells harbor an unexplored plasticity in their fatty acid metabolism.
Here, we discover that some cancer cells can exploit an alternative fatty acid
desaturation pathway. We identify various cancer cell lines, murine
hepatocellular carcinomas (HCC), and primary human liver and lung carcinomas
that desaturate palmitate to the unusual fatty acid sapienate to support
membrane biosynthesis during proliferation. Accordingly, we found that sapienate
biosynthesis enables cancer cells to bypass the known stearoyl-CoA desaturase
(SCD)-dependent fatty acid desaturation. Thus, only by targeting both
desaturation pathways the
in vitro
and
in vivo
proliferation of sapienate synthesizing cancer cells is impaired. Our discovery
explains metabolic plasticity in fatty acid desaturation and constitutes an
unexplored metabolic rewiring in cancers.
The catabolism rates of a medium chain fatty acid (octanoic acid), an even‐numbered fatty acid (palmitic acid), and odd‐numbered fatty acids (pentadecanoic acid and heptadecanoic acid) in mice were compared using stable isotope (13C) labeled fatty acids and isotope‐ratio MS (IRMS). The catabolism rates of respective fatty acids were evaluated by the ratio of 13C and 12C in carbon dioxide expired from mice. The results show that the catabolism rate of octanoic acid is three times faster than that of palmitic acid. This result is in agreement with previous knowledge that medium chain fatty acids are easily beta‐oxidized as compared to long chain fatty acids. The catabolism rates of odd‐numbered fatty acids such as pentadecanoic acid and heptadecanoic acid were significantly lower as compared to those of even‐numbered fatty acids such as palmitic acid. This finding supports our previous report that odd‐numbered fatty acids are easily accumulated into body fat. The high accumulation of odd‐numbered fatty acids in body fat would be a direct result of their low beta‐oxidizability.Practical applications: 13C‐labeled fatty acids were administered to mice and the rates of 13CO2 formation were compared among medium chain, even‐numbered, and odd‐numbered fatty acids using IRMS. We found that the catabolism rates of odd‐numbered fatty acids such as pentadecanoic acid and heptadecanoic acid were significantly lower in comparison to those of even‐numbered fatty acids such as palmitic acid. These findings could be valuable for the development of the lipid metabolism field.
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