Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer

Abstract

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

Lipid Metabolism and Ferroptosis

“…Transcriptome analysis suggested that there were no significant changes in the levels of fatty acid transporters during this process. Interestingly, we found that FATP2 levels are relatively low in mesenchymal-type GC cells, implying that fatty acid import is somewhat limited in these cells; therefore, these cells are dependent on PUFA biosynthesis [63]. Although AA is regarded as a primary target for lipid peroxidation, ELOVL5-depleted GC cells still contain comparable amounts of AA and PE-AA, possibly activating AA import [63].…”

“…AA and AdA are ω-6 fatty acids and can be synthesized from linoleic acid (LA) through the ω-6 de novo PUFA synthesis pathway using ELOVL2, ELOVL5, FADS1 and FADS2 (Figure 2a). These enzymes seem to play an essential role in ferroptosis [63,64]. In particular, intestinal-type gastric cancer (GC) cells express extremely low levels of ELOVL5 and FADS1 due to hypermethylation at the promoter region and are resistant to ferroptosis, while mesenchymal-type GC cells are sensitive to ferroptosis at high levels of ELOVL5 and FADS1 [63].…”

“…These enzymes seem to play an essential role in ferroptosis [63,64]. In particular, intestinal-type gastric cancer (GC) cells express extremely low levels of ELOVL5 and FADS1 due to hypermethylation at the promoter region and are resistant to ferroptosis, while mesenchymal-type GC cells are sensitive to ferroptosis at high levels of ELOVL5 and FADS1 [63]. Isotope-tracing analysis clearly proposed that intestinal-type cells are defective in synthesizing AA and AdA from LA, but these cells become sensitive to ferroptosis upon supplementation with AA [63].…”

“…In particular, intestinal-type gastric cancer (GC) cells express extremely low levels of ELOVL5 and FADS1 due to hypermethylation at the promoter region and are resistant to ferroptosis, while mesenchymal-type GC cells are sensitive to ferroptosis at high levels of ELOVL5 and FADS1 [63]. Isotope-tracing analysis clearly proposed that intestinal-type cells are defective in synthesizing AA and AdA from LA, but these cells become sensitive to ferroptosis upon supplementation with AA [63]. Analysis of The Cancer Cell Line Encyclopedia (CCLE) database suggested that ELOVL5 and FADS1 are expressed in most cancer cells, but those genes are silenced in some types of cancer cells, including gastric and colorectal cancer cells, suggesting that these two enzymes could be used as prediction markers for ferroptosis-mediated cancer therapy [63].…”

“…Isotope-tracing analysis clearly proposed that intestinal-type cells are defective in synthesizing AA and AdA from LA, but these cells become sensitive to ferroptosis upon supplementation with AA [63]. Analysis of The Cancer Cell Line Encyclopedia (CCLE) database suggested that ELOVL5 and FADS1 are expressed in most cancer cells, but those genes are silenced in some types of cancer cells, including gastric and colorectal cancer cells, suggesting that these two enzymes could be used as prediction markers for ferroptosis-mediated cancer therapy [63]. Moreover, depletion or inhibition of FADS2 inhibits RSL3-induced ferroptosis [63,64].…”