Open Access Highly Accessed Research article

Different fatty acid metabolism effects of (−)-Epigallocatechin-3-Gallate and C75 in Adenocarcinoma lung cancer

Joana Relat1, Adriana Blancafort2, Glòria Oliveras23, Sílvia Cufí3, Diego Haro1, Pedro F Marrero1 and Teresa Puig2*

Author Affiliations

1 Biochemistry and Molecular Biology, School of Pharmacy and Institute of Biomedicine of the University of Barcelona (IBUB), 08028, Barcelona, Spain

2 Molecular Oncology (NEOMA), School of Medicine, University of Girona and Girona Institute for Biomedical Research (IDIBGi), 17071, Girona, Spain

3 Molecular Oncology, Catalan Institute of Oncology (ICO), Girona Institute for Biomedical Research (IDIBGi), 17007, Girona, Spain

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BMC Cancer 2012, 12:280  doi:10.1186/1471-2407-12-280

Published: 6 July 2012

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords:
Lung cancer; Xenograft; Fatty acid synthase; EGCG; C75; Inhibitors; Weight loss; Fatty acid metabolism; EGFR