FSCN1 Modulates Fatty Acid Metabolism and the Coordinated Activation of AKT/mTOR and p38 MAPK Pathways in Colorectal Cancer Cells.

Background

Fascin actin-bundling protein 1 (FSCN1) modulates the expression of key lipogenic enzymes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1) in colorectal cancer (CRC), but the underlying mechanisms remain elusive.

Methods

Bioinformatics analyses were performed to evaluate FSCN1 expression and its prognostic value in CRC. Intracellular lipid levels following FSCN1 knockdown were assessed by Nile Red/DAPI co-staining and triglyceride quantification, and further validated by Oil Red O staining of xenograft tumors. Expression levels of key metabolic enzymes were measured by qRT-PCR and Western blotting. RNA sequencing identified FSCN1-associated pathways, which were functionally investigated using pharmacological inhibitors.

Results

FSCN1 was significantly upregulated in CRC (p < 0.001; AUC = 0.796) and was correlated with poorer overall survival (p = 0.018). FSCN1 depletion reduced intracellular lipid accumulation, accompanied by downregulation of lipogenic mediators-sterol regulatory element-binding transcription factor 1 (SREBF1; protein product: SREBP1), FASN, and SCD1-and upregulation of peroxisomal fatty acid oxidation (FAO)-related factors-peroxisome proliferator-activated receptor alpha (PPARA; protein product: PPARα) and acyl-CoA oxidase 1 (ACOX1). Mechanistically, FSCN1 was associated with activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) and p38 mitogen-activated protein kinase (p38 MAPK) pathways; pharmacological inhibition with LY294002 or SB203580 phenocopied the lipid-lowering effects of FSCN1 knockdown.

Conclusion

Collectively, these findings link FSCN1 to the AKT/mTOR/SREBP1/(FASN/SCD1) lipogenic axis and the p38 MAPK/PPARα/ACOX1 peroxisomal FAO pathway, implicating FSCN1 in lipid metabolic regulation and CRC progression, while suggesting a putative functional regulatory axis and a promising candidate therapeutic target for CRC.