Theanaphthoquinone inhibits fatty acid synthase expression in EGF-stimulated human breast cancer cells via the regulation of EGFR/ErbB-2 signaling.

Abstract

Fatty acid synthase (FAS) is a major lipogenic enzyme catalyzing the synthesis of long-chain saturated fatty acids. Most breast cancers require lipogenesis for growth. Here, we demonstrated the effects of theanaphthoquinone (TNQ), a member of the thearubigins generated by the oxidation of theaflavin (TF-1), on the expression of FAS in human breast cancer cells. TNQ was found to suppress the EGF-induced expression of FAS mRNA and FAS protein in MDA-MB-231 cells. Expression of FAS has previously been shown to be regulated by the SREBP family of transcription factors. In this study, we demonstrated that the EGF-induced nuclear translocation of SREBP-1 was blocked by TNQ. Moreover, TNQ also modulated EGF-induced ERK1/2 and Akt phosphorylation. Treatment of MDA-MB-231 cells with PI 3-kinase inhibitors, LY294002 and Wortmannin, inhibited the EGF-induced expression of FAS and nuclear translocation of SREBP-1. Treatment with TNQ inhibited EGF-induced EGFR/ErbB-2 phosphorylation and dimerization. Furthermore, treatment with kinase inhibitors of EGFR and ErbB-2 suggested that EGFR/ErbB-2 activation was involved in EGF-induced FAS expression. In constitutive FAS expression, TNQ inhibited FAS expression and Akt autophosphorylation in BT-474 cells. The PI 3-kinase inhibitors and tyrosine kinase inhibitors of EGFR and ErbB-2 also reduced constitutive FAS expression. In addition, pharmacological blockade of FAS by TNQ decreased cell viability and induced cell death in BT-474 cells. In summary, our findings suggest that TNQ modulates FAS expression by the regulation of EGFR/ErbB-2 pathways and induces cell death in breast cancer cells.

• Authors: Meng-Shih Weng, Chi-Tang Ho, Yuan-Soon Ho, Jen-Kun Lin
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 218 Issue 2 Pg. 107-18 (Jan 15 2007) ISSN: 0041-008X [Print] United States
• PMID: 17182072 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Naphthoquinones
• Sterol Regulatory Element Binding Protein 1
• fas Receptor
• theanaphthoquinone
• Tyrosine
• Epidermal Growth Factor
• Fatty Acid Synthases
• Phosphatidylinositol 3-Kinases
• ErbB Receptors
• Oncogene Protein v-akt

Topics

• Blotting, Western
• Breast Neoplasms (metabolism, pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Nucleus (drug effects, ultrastructure)
• Cell Survival (drug effects)
• Down-Regulation (physiology)
• Epidermal Growth Factor (pharmacology)
• ErbB Receptors (genetics)
• Fatty Acid Synthases (antagonists & inhibitors)
• Female
• Flow Cytometry
• Genes, erbB-2 (genetics)
• Humans
• Immunoprecipitation
• Naphthoquinones (pharmacology)
• Oncogene Protein v-akt (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Sterol Regulatory Element Binding Protein 1 (genetics, metabolism)
• Stimulation, Chemical
• Translocation, Genetic
• Tyrosine (metabolism)
• fas Receptor (biosynthesis)