Unsaturated Fatty Acids Stimulate Tumor Growth through Stabilization of β-Catenin

Abstract

Summary Some cancer cells exhibit elevated levels of free fatty acids (FAs) as well as high levels of β-catenin, a transcriptional co-activator that promotes their growth. Here we link these two phenomena by showing that unsaturated FAs inhibit degradation of β-catenin. Unsaturated FAs bind to the UAS domain of Fas-associated factor 1 (FAF1), a protein known to bind β-catenin, accelerating its degradation. FA binding disrupts the FAF1/β-catenin complex, preventing proteasomal degradation of ubiquitinated β-catenin. This mechanism for stabilization of β-catenin differs from that of Wnt signaling, which blocks ubiquitination of β-catenin. In clear cell renal cell carcinoma (ccRCC) cells, unsaturated FAs stimulated cell proliferation through stabilization of β-catenin. In tissues from biopsies of human ccRCC, elevated levels of unsaturated FAs correlated with increased levels of β-catenin. Thus, targeting FAF1 may be an effective approach to treat cancers that exhibit elevated FAs and β-catenin.

Wnt4 antagonises Wnt3a mediated increases in growth and glucose stimulated insulin secretion in the pancreatic beta-cell line, INS-1

“…As Wnt4 did not increase levels of 'active' β-catenin, the increased β-catenin seen with Wnt4 is presumably still phosphorylated by GSK3β, suggest that Wnt4 may disrupt the ubiquitin proteasome pathway or stabilise β-catenin by phosphorylating the protein on a different residue. This GSK3β independent stabilisation of β-catenin has recently been described in tumour cells in response to unsaturated fatty acids in [28].…”

Oleic acid promotes prostate cancer malignant phenotype via the G protein‐coupled receptor FFA1/GPR40

“…Intriguingly, the attenuation of FFA1/GPR40 expression by transfecting PC3 cells with the Sh3 construct was able to prevent Akt phosphorylation by OA (Figure ), suggesting that OA induced the PI3K/Akt pathway activation via FFA1/GPR40. It has been recently described that increased FFA levels can affect clear cell renal cell carcinoma proliferation through β‐catenin stabilization (Kim et al, ). However, we did not observe the increase of β‐catenin following OA treatment in our cellular system (Supplementary Figure S1).…”

Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism

“…Kwan et al reported the opposite observation, that C16:0 promoted melanoma growth by activating Akt signaling in a phosphatase and tensin homolog–independent manner . On the other hand, unsaturated fatty acid C18:1 was reported to stimulate tumor growth through stabilization of β‐catenin . Other research has provided evidence that C16:0 is lipotoxic and mediates steatohepatitis or nonalcoholic fatty liver disease .…”