Up-regulation of Acetyl-CoA Carboxylase α and Fatty Acid Synthase by Human Epidermal Growth Factor Receptor 2 at the Translational Level in Breast Cancer Cells
Copyright policy )Up-regulation of Acetyl-CoA Carboxylase α and Fatty Acid Synthase by Human Epidermal Growth Factor Receptor 2 at the Translational Level in Breast Cancer Cells
Expression of the HER2 oncogene is increased in approximately 30% of human breast carcinomas and is closely correlated with the expression of fatty acid synthase (FASN). In the present study, we determined the mechanism by which FASN and acetyl-CoA carboxylase alpha (ACCalpha) could be induced by HER2 overexpression. SK-BR-3 and BT-474 cells, breast cancer cells that overexpress HER2, expressed higher levels of FASN and ACCalpha compared with MCF-7 and MDA-MB-231 breast cancer cells in which HER2 expression is low. The induction of FASN and ACCalpha in BT474 cells were not mediated by the activation of SREBP-1. Exogenous HER2 expression in MDA-MB-231 cells induced the expression of FASN and ACCalpha, and the HER2-mediated increase in ACCalpha and FASN was inhibited by both LY294002, a phosphatidylinositol 3-kinase inhibitor, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. In addition, the activation of mTOR by the overexpression of RHEB in MDA-MB-231 cells increased the synthetic rates of both FASN and ACCalpha. On the other hand, FASN and ACCalpha were reduced in BT-474 cells by a blockade of the mTOR signaling pathway. These changes observed in their protein levels were not accompanied by changes in their mRNA levels. The 5'- and 3'-untranslated regions of both FASN and ACCalpha mRNAs were involved in selective translational induction that was mediated by mTOR signal transduction. These results strongly suggest that the major mechanism of HER2-mediated induction of FASN and ACCalpha in the breast cancer cells used in this study is translational regulation primarily through the mTOR signaling pathway.
- Yonsei University Medical Library Korea (Republic of)
- Yonsei University Korea (Republic of)
- Yonsei University Health System Korea (Republic of)
ErbB-2/metabolism*, Receptor, ErbB-2, ErbB Receptors/genetics, Enzyme Induction/drug effects, 5' Untranslated Regions/metabolism, 3' Untranslated Regions/metabolism, Acetyl-CoA Carboxylase/biosynthesis*, Phosphatidylinositol 3-Kinases, RNA, Neoplasm, Enzyme Inhibitors, 5' Untranslated Regions/genetics, Signal Transduction*/drug effects, 3' Untranslated Regions, Phosphoinositide-3 Kinase Inhibitors, Enzyme Inhibitors/pharmacology, ErbB Receptors/metabolism, Tumor, TOR Serine-Threonine Kinases, ErbB Receptors, Gene Expression Regulation, Neoplastic, Neoplasm/metabolism, 3' Untranslated Regions/genetics, Enzyme Induction, Protein Kinases/metabolism, Female, Morpholines/pharmacology, Phosphatidylinositol 3-Kinases/metabolism, Receptor, ErbB-2/genetics, Morpholines, 610, Breast Neoplasms, Breast Neoplasms/enzymology*, Breast Neoplasms/genetics, Phosphatidylinositol 3-Kinases/antagonists & inhibitors, Cell Line, Sterol Regulatory Element Binding Protein 1/genetics, Cell Line, Tumor, Fatty Acid Synthases/biosynthesis*, Humans, Neoplastic*/drug effects, Neoplasm/genetics, Sterol Regulatory Element Binding Protein 1/metabolism, Fatty Acid Synthases/genetics, Protein Biosynthesis*/drug effects, Acetyl-CoA Carboxylase/genetics, Gene Expression Regulation, Chromones, Protein Biosynthesis, RNA, Chromones/pharmacology, Fatty Acid Synthases, 5' Untranslated Regions, Protein Kinases, Acetyl-CoA Carboxylase
ErbB-2/metabolism*, Receptor, ErbB-2, ErbB Receptors/genetics, Enzyme Induction/drug effects, 5' Untranslated Regions/metabolism, 3' Untranslated Regions/metabolism, Acetyl-CoA Carboxylase/biosynthesis*, Phosphatidylinositol 3-Kinases, RNA, Neoplasm, Enzyme Inhibitors, 5' Untranslated Regions/genetics, Signal Transduction*/drug effects, 3' Untranslated Regions, Phosphoinositide-3 Kinase Inhibitors, Enzyme Inhibitors/pharmacology, ErbB Receptors/metabolism, Tumor, TOR Serine-Threonine Kinases, ErbB Receptors, Gene Expression Regulation, Neoplastic, Neoplasm/metabolism, 3' Untranslated Regions/genetics, Enzyme Induction, Protein Kinases/metabolism, Female, Morpholines/pharmacology, Phosphatidylinositol 3-Kinases/metabolism, Receptor, ErbB-2/genetics, Morpholines, 610, Breast Neoplasms, Breast Neoplasms/enzymology*, Breast Neoplasms/genetics, Phosphatidylinositol 3-Kinases/antagonists & inhibitors, Cell Line, Sterol Regulatory Element Binding Protein 1/genetics, Cell Line, Tumor, Fatty Acid Synthases/biosynthesis*, Humans, Neoplastic*/drug effects, Neoplasm/genetics, Sterol Regulatory Element Binding Protein 1/metabolism, Fatty Acid Synthases/genetics, Protein Biosynthesis*/drug effects, Acetyl-CoA Carboxylase/genetics, Gene Expression Regulation, Chromones, Protein Biosynthesis, RNA, Chromones/pharmacology, Fatty Acid Synthases, 5' Untranslated Regions, Protein Kinases, Acetyl-CoA Carboxylase
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