Portal de Periódicos da CAPES

Fatty acid metabolism in cancer cells: Differential inhibitory effects of epigallocatechin (EGCG) and C75

2006; American Association for Cancer Research; Volume: 12; Linguagem: Inglês

1557-3265

Teresa Puig, Alejandro Vázquez‐Martín, Pedro F. Marrero, Gemma Casals, Jordi Pétriz, Joana Relat, Diego Haro, Javier A. Menéndez, María L. López-Rodrı́guez, María Vilanova, Rámón Colomer,

Metabolomics and Mass Spectrometry Studies

B28 Endogenous fatty acid metabolism is crucial to maintain the cancer cell malignant phenotype. We and others have shown that blocking the activity of fatty acid synthase (FASN), a lipogenic multienzyme that catalyzes the final step in the de novo fatty acid synthesis, either alone or in combination with chemoterapy or monoclonal antibodies, has potential as an anticancer strategy. The pharmacologic FASN inhibitors, cerulenin and its synthetic derivative C75, show a structurally-related weight-loss induction in experimental animals, which limits in clinical development. Other compounds that block FASN activity include (-)-epigallocatechin-3-gallate (EGCG), triclosan and orlistat.We have tested whether there are differential effects of EGCG in comparison with C75 on fatty acid metabolism (FASN, and carnitine palmitoyltransferase-1 [CPT-1], a component of the shuttle system which allows entry of long-chain fatty acids into the mitochondrial matrix for subsequent oxidation), and on cellular and molecular effects in three metastatic breast cancer cell lines MDA-MB-231, MCF-7 and SK-Br3, which are models of low, moderate and high levels of FAS, respectively. EGCG and C75 had comparable effects in blocking FASN, producing a dose- and time-dependent decrease in the viability of metastatic breast cancer cell lines MDA-MB-231, MCF-7 and SK-Br3 (directly dependent on cell FAS levels); causing a decrease in the active forms of oncoprotein HER2, AKT and ERK1/2, and inducing apoptosis (as assessed by cleavage of PARP and flow cytometry using Annexin V conjugated to Alexa Fluor 488 and propidium iodide).We observed, in contrast, clear differential effects between EGCG and C75 on CPT-1 activity. While EGCG has either no effect or a moderate reduction in CPT-1 activity, C75 stimulated CPT-1 activity (up to 125 %). Our results with EGCG show that pharmacologically inhibition of FAS can occur uncoupled from the stimulation of CPT-1, and thus avoid the weight-loss pathways. We are now evaluating the combination of EGCG with chemotherapy and monoclonal antibodies.