Diet-induced alteration of fatty acid synthase in prostate cancer progression.
Diet-induced alteration of fatty acid synthase in prostate cancer progression.
复制标题
饮食诱导的前列腺癌进展中脂肪酸合酶的改变。
DOI：
10.1038/oncsis.2015.42
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发表时间：
2016-02-15
期刊：
影响因子：
6.2
通讯作者：
Habuchi, T.
中科院分区：
文献类型：
--
作者：
Huang, M.;Koizumi, A.;Narita, S.;Inoue, T.;Tsuchiya, N.;Nakanishi, H.;Numakura, K.;Tsuruta, H.;Saito, M.;Satoh, S.;Nanjo, H.;Sasaki, T.;Habuchi, T.
脂肪酸合酶（FASN）是一种催化脂肪酸从头合成的胞质代谢酶。高脂肪饮食 (HFD) 与前列腺癌 (PCa) 进展有关，但 FASN 在 HFD 介导的 PCa 进展中的作用仍不清楚。我们研究了 FASN 对 HFD 或低脂饮食 (LFD) 喂养的 LNCaP 异种移植小鼠、PCa 细胞和临床 PCa 进展的作用。 HFD 促进 LNCaP 异种移植小鼠的肿瘤生长和 FASN 表达。 HFD 导致 AKT 和细胞外信号调节激酶 (ERK) 激活以及 5' 腺苷单磷酸激活蛋白激酶 (AMPK) 失活。 HFD 组血清 FASN 水平显着降低（P=0.026），并且与肿瘤体积呈反比（P=0.022）。通过磷脂酰肌醇 3 激酶 (PI3K)/丝裂原激活蛋白激酶 (MAPK) 抑制和 AMPK 信号激活，PCa 细胞中细胞外 FASN 释放得到增强。 FASN 抑制通过 PI3K/MAPK 下调和 AMPK 激活导致 PCa 细胞增殖减少。此外，AMPK 激活与 FASN 下调和 PI3K/MAPK 失活相关。临床上，FASN 高表达与高 Gleason 评分和晚期病理 T 分期显着相关。此外，PCa 对雄激素剥夺疗法和化疗的反应中 FASN 表达显着降低。 HFD 调节 FASN 表达，这可能是 HFD 相关 PCa 进展的重要机制。此外，FASN 和 PI3K/MAPK 系统之间存在关键的刺激环路，而 AMPK 信号传导则与抑制相关。这些可能为 HFD 诱导的 PCa 的化学预防和癌症治疗提供适当的靶点。
Fatty acid synthase (FASN) is a cytosolic metabolic enzyme that catalyzes de novo fatty acid synthesis. A high-fat diet (HFD) is attributed to prostate cancer (PCa) progression, but the role FASN on HFD-mediated PCa progression remains unclear. We investigated the role of FASN on PCa progression in LNCaP xenograft mice fed with HFD or low-fat diet (LFD), in PCa cells, and in clinical PCa. The HFD promoted tumour growth and FASN expression in the LNCaP xenograft mice. HFD resulted in AKT and extracellular signal-regulated kinase (ERK) activation and 5' adenosine monophosphate-activated protein kinase (AMPK) inactivation. Serum FASN levels were significantly lower in the HFD group (P=0.026) and correlated inversely with tumour volume (P=0.022). Extracellular FASN release was enhanced in the PCa cells with phosphatidylinositol 3-kinase (PI3K)/mitogen-activated protein kinase (MAPK) inhibition and AMPK signalling activation. FASN inhibition resulted in decrease of PCa cell proliferation through PI3K/MAPK downregulation and AMPK activation. Furthermore, AMPK activation was associated with FASN downregulation and PI3K/MAPK inactivation. Clinically, high FASN expression was significantly associated with high Gleason scores and advanced pathological T stage. Moreover, FASN expression was markedly decreased in the PCa response to androgen deprivation therapy and chemotherapy. HFD modulates FASN expression, which may be an important mechanism in HFD-associated PCa progression. Furthermore, a critical stimulatory loop exists between FASN and the PI3K/MAPK system, whereas AMPK signalling was associated with suppression. These may offer appropriate targets for chemoprevention and cancer therapy in HFD-induced PCa.
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