Drug Discov Ther. 2023;17(5):328-339. (DOI: 10.5582/ddt.2023.01036)

FASN promotes gallbladder cancer progression and reduces cancer cell sensitivity to gemcitabine through PI3K/AKT signaling

Cheng HH, Sun YX, Yu XP, Zhou D, Ding J, Wang SH, Ma F


Lipid metabolism plays an important role in the growth and development of tumors. However, the role of lipid metabolism in gallbladder cancer (GBC) has not been clearly clarified. Here, we demonstrated that fatty acid synthase (FASN), a key enzyme in de novo fatty acid biosynthesis, had upregulated expression in GBC samples both at protein and mRNA levels. Analysis of clinical data indicated the association between elevated FASN expression and poorer histology grades. Furthermore, FASN activity impairment through FASN knockdown or treatment with orlistat resulted in the inhibition of cell proliferation and migration, as well as increased sensitivity to gemcitabine. Both FASN knockdown and orlistat treatment induced cell apoptosis. Mechanistically, impairment of FASN activity suppressed the activation of the PI3K/AKT signaling pathway, which led to increased cell apoptosis and sensitivity to gemcitabine. These findings were also validated through nude mouse xenograft models, thus highlighting the potential of targeting FASN as a clinical treatment strategy. Collectively, the present study underscores the crucial role of FASN in the progression of gallbladder cancer via the PI3K/AKT pathway.

KEYWORDS: GBC, orlistat, drug combination

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