Different fatty acid metabolism effects of (-)-epigallocatechin-3-gallate and C75 in adenocarcinoma lung cancer.
Different fatty acid metabolism effects of (-)-epigallocatechin-3-gallate and C75 in adenocarcinoma lung cancer.
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DOI：
10.1186/1471-2407-12-280
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发表时间：
2012-07-06
期刊：
影响因子：
3.8
通讯作者：
Puig T
中科院分区：
文献类型：
--
作者：
Relat J;Blancafort A;Oliveras G;Cufí S;Haro D;Marrero PF;Puig T
脂肪酸合成酶（FASN）在包括肺癌在内的几种人类癌症中过度表达和过度激活。我们在肺癌模型中表征并比较了FASN抑制剂C75和(−)-表没食子儿茶素-3-没食子酸酯（EGCG）的抗癌作用。我们在体外评估了C75和EGCG对人A549肺癌细胞脂肪酸代谢（FASN和CPT酶）、细胞增殖、细胞凋亡和细胞信号传导（EGFR、ERK1/2、AKT和mTOR）的影响。在体内，我们在人类腺癌异种移植小鼠模型中评估了它们的抗肿瘤活性及其对体重的影响。C75和EGCG在抑制FASN活性方面具有相当的效果（分别为96.9%和89.3%）。相比之下，EGCG对脂肪酸β-氧化限速酶CPT活性无显著影响，而C75对CPT活性的刺激高达130%。用EGCG或C75治疗肺癌细胞可诱导细胞凋亡并影响egfr信号传导。虽然EGCG可以抑制p-EGFR、p-AKT、p-ERK1/2和p-mTOR，但C75在降低EGFR和p-AKT水平方面的活性较低。在体内，EGCG和C75阻断了肺癌异种移植物的生长，但C75治疗，而不是EGCG治疗，导致动物体重明显减轻。在肺癌中，EGCG对FASN的抑制可以在不同时刺激脂肪酸氧化的情况下实现，这种作用主要与EGFR信号通路有关。EGCG可抑制腺癌生长，但不引起体重下降。综上所述，EGCG可能是未来临床前开发的候选药物。
Fatty acid synthase (FASN) is overexpressed and hyperactivated in several human carcinomas, including lung cancer. We characterize and compare the anti-cancer effects of the FASN inhibitors C75 and (−)-epigallocatechin-3-gallate (EGCG) in a lung cancer model. We evaluated in vitro the effects of C75 and EGCG on fatty acid metabolism (FASN and CPT enzymes), cellular proliferation, apoptosis and cell signaling (EGFR, ERK1/2, AKT and mTOR) in human A549 lung carcinoma cells. In vivo, we evaluated their anti-tumour activity and their effect on body weight in a mice model of human adenocarcinoma xenograft. C75 and EGCG had comparable effects in blocking FASN activity (96,9% and 89,3% of inhibition, respectively). In contrast, EGCG had either no significant effect in CPT activity, the rate-limiting enzyme of fatty acid β-oxidation, while C75 stimulated CPT up to 130%. Treating lung cancer cells with EGCG or C75 induced apoptosis and affected EGFR-signaling. While EGCG abolished p-EGFR, p-AKT, p-ERK1/2 and p-mTOR, C75 was less active in decreasing the levels of EGFR and p-AKT. In vivo, EGCG and C75 blocked the growth of lung cancer xenografts but C75 treatment, not EGCG, caused a marked animal weight loss. In lung cancer, inhibition of FASN using EGCG can be achieved without parallel stimulation of fatty acid oxidation and this effect is related mainly to EGFR signaling pathway. EGCG reduce the growth of adenocarcinoma human lung cancer xenografts without inducing body weight loss. Taken together, EGCG may be a candidate for future pre-clinical development.
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影响因子：
6.4
作者：
Brusselmans, K;De Schrijver, E;Swinnen, JV
通讯作者：
Swinnen, JV
影响因子：
8.8
作者：
Petroulakis, E;Mamane, Y;Le Bacquer, O;Shahbazian, D;Sonenberg, N
通讯作者：
Sonenberg, N
影响因子：
3.8
作者：
Puig, Teresa;Vazquez-Martin, Alejandro;Colomer, Ramon
通讯作者：
Colomer, Ramon
影响因子：
3.3
作者：
Piyathilake, CJ;Frost, AR;Grizzle, WE
通讯作者：
Grizzle, WE
影响因子：
5.2
作者：
Huang, Chi-Hung;Tsai, Shang-Jie;Way, Tzong-Der
通讯作者：
Way, Tzong-Der