EMBO J: Li Binghui's team at Capital Medical University found that stearate-derived ultra-long-chain fatty acids affect tumor growth

Reprogramming of lipid metabolism is becoming a hallmark feature of cancer, but the mechanisms by which specific fatty acid (FA) species and associated enzymes play in tumorigenesis remain unclear
.
While previous studies have focused on the role of long-chain fatty acids (LCFAs) such as palmitic acid in cancer, little attention has been paid to the role of ultra-long-chain fatty acids (VLCFAs).

On November and 21, 2022, Li Binghui's team from Capital Medical University published an online title in EMBO Journal (IF=14).
"Stearate-derived very long-chain fatty acids are indispensable to tumor growth," a study showing acetyl-CoA carboxylase (ACC1,).
The loss of a key enzyme involved in fatty acid biosynthesis), inhibiting de novo synthesis and extension
of VLCFAs in human cancer cells.
ACC1 deletion significantly reduced cellular VLCFA but only slightly affected LCFA levels, including palmitates
, which are of nutritional value.
Therefore, tumor growth is very sensitive
to the regulation of VLCFA.

Further studies showed that VLCFA deficiency resulted in a significant reduction in ceramide as well as downstream glucosylceramide and sphingomyelin, which impair mitochondrial morphology and sensitize cancer cells to oxidative stress and cell death
.
Taken together, the study highlights VLCFA as a selective need for cancer cell survival and reveals a potential strategy
to inhibit tumor growth.

Fatty acids are a group of different aliphatic hydrocarbons with polar carboxyl end groups
.
These molecules vary in length, number of carbon atoms, and saturation, including the number and location
of double bonds.
Based on saturation, fatty acids can be unanied, have one double bond, or contain more than one double bond, called saturated (SFAs), monounsaturated (MUFAs), and polyunsaturated fatty acids (PUFAs), respectively
.
Mammalian cells can synthesize fatty acids de novo from acetyl-CoA, which is mainly derived from glucose, glutamine and acetic acid
.
Subsequently, acetyl-CoA is converted to malonyl-CoA by acetyl-CoA
carboxylase.

There are two isoenzymes, acetyl-CoA carboxylase 1 (ACC1) and acetyl-CoA carboxylase 2 (ACC2), that mediate unique physiological functions
within cells.
ACC1 is mainly localized to cytosols, while ACC2 is associated
with the outer mitochondrial membrane.
Thus, ACC1 produces malonyl-CoA in the cytoplasm, which is the main carbon donor for fatty acid synthesis
.
Seven malonyl-CoA molecules act as extension units, together with acetyl-CoA as a starter, catalyzed by fatty acid synthase (FASN) to form a 16-carbon saturated fatty acid palmitate
。 In contrast, malonyl-CoA synthesized by ACC2 is located near the surface of mitochondria and is thought to be an inhibitor of carnitine palmitoyl transferase 1 (CPT1), thereby regulating the transport of long-chain fatty acids to mitochondria for subsequent use β - oxidation
.

Mechanisms by which ultra-long-chain fatty acids (VLCFAs) and acetyl-CoA carboxylase (ACC1) promote tumor growth (from EMBO Journal).

Mammalian cells can use stearoyl-CoA desaturase (SCD) to create double bonds at the D9 location of the hydrocarbon chain, forming n-9 MUFAs such as palmitate and oleate
.
However, these cells do not have the ability to
produce unsaturated fatty acids with double bonds at the D3 or D6 positions.
Therefore, mammalian cells must ingest n-3 and n-6 unsaturated fatty acids (mainly linoleic acid and α-linolenic acid) as essential nutrients
.
These fatty acids can be further extended into very long chain fatty acids (VLCFAs, C≥22
).

The extension of VLCFAs occurs mainly in the endoplasmic reticulum (ER), by repeating the extension cycle, i.
e.
by extenders (extension of extra-long fatty acids, ELOVL1-7), 3- Acetylacyl-CoA reductase (KAR), 3-hydroxyacyl-CoA dehydratase (HACD1-4).
and trans-2-enoyl-CoA reductase (TECR)-catalyzed four consecutive transformations
.
Although polyunsaturated fatty acids can be produced by fatty acid desaturationase (FADS1-3) and extend mainly from the dietary essential linoleic acid and α-linolenic acid, many essential polyunsaturated fatty acids must be obtained
from outside the body.

The reprogramming of lipid metabolism is becoming one
of the hallmarks of cancer.
The role of ectopic de novo fatty acid synthesis in cancer has been extensively studied over the past few decades, and the enzymes ACC1 and FASN involved are considered potential anti-tumor targets
.
However, it is still necessary to determine how these enzymes involved in fatty acid synthesis affect cellular lipid metabolism
.
The study performed lipid metabolomic analysis of FASN knockout and ACC1/2 knockout cells and systematically compared these data
.
It was finally revealed that tumor growth was susceptible to the regulation of VLCFAs rather than LCFAs (including palmitates), and further dissected the underlying mechanisms:

1.
ACC1 depletion can reduce VLCFA reduction, but does not reduce the level of
long-chain fatty acids in human cancer cells.

2.
VLCFA elongation can enhance tumor growth
in xenograft models.

3.
VLCFA deficiency leads to a significant reduction
in ceramide and downstream glucosylceramide and sphingomyelin.

4.
VLCFA deficiency can damage mitochondrial morphology and make cancer cells sensitive
to oxidative stress.

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