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

IF 1.9 Q3 PHARMACOLOGY & PHARMACY Drug Discoveries and Therapeutics Pub Date : 2023-11-18 Epub Date: 2023-09-22 DOI:10.5582/ddt.2023.01036
Haihong Cheng, Yuxin Sun, Xiaopeng Yu, Di Zhou, Jun Ding, Shouhua Wang, Fei Ma
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Abstract

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.

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FASN通过PI3K/AKT信号促进胆囊癌症进展并降低癌症细胞对吉西他滨的敏感性。
脂质代谢在肿瘤的生长发育中起着重要作用。然而,脂质代谢在胆囊癌症(GBC)中的作用尚未明确。在这里,我们证明了脂肪酸合成酶(FASN),一种新脂肪酸生物合成的关键酶,在GBC样品中的蛋白质和mRNA水平上都上调了表达。临床数据分析表明FASN表达升高与组织学分级较差之间存在关联。此外,通过FASN敲除或用奥利司他治疗引起的FASN活性损伤导致细胞增殖和迁移的抑制,以及对吉西他滨的敏感性增加。FASN敲除和奥利司他治疗均诱导细胞凋亡。从机制上讲,FASN活性的损伤抑制了PI3K/AKT信号通路的激活,从而导致细胞凋亡和对吉西他滨的敏感性增加。这些发现也通过裸鼠异种移植物模型得到了验证,从而突出了靶向FASN作为临床治疗策略的潜力。总之,本研究强调了FASN通过PI3K/AKT途径在胆囊癌症进展中的关键作用。
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来源期刊
Drug Discoveries and Therapeutics
Drug Discoveries and Therapeutics PHARMACOLOGY & PHARMACY-
CiteScore
3.20
自引率
3.20%
发文量
51
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