title: Up-regulation of acetyl-CoA carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science, Institute of Genetic Science, Center for Chronic Metabolic Disease Research, Seoul, Korea.
authors.forename: Sarah
authors.initials: S
authors.lastname: Yoon
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Lee
authors.forename: Sahng Wook
authors.initials: SW
authors.lastname: Park
authors.forename: Jong-Seok
authors.initials: JS
authors.lastname: Moon
authors.forename: Yoo-Kyung
authors.initials: YK
authors.lastname: Koh
authors.forename: Yong-Ho
authors.initials: YH
authors.lastname: Ahn
authors.forename: Byeong-Woo
authors.initials: BW
authors.lastname: Park
authors.forename: Kyung-Sup
authors.initials: KS
authors.lastname: Kim
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics / Q000378:metabolism; D020121:5' Untranslated Regions / Q000235:genetics / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000103:Acetyl-CoA Carboxylase; D002867:Chromones; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D064429:Fatty Acid Synthases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D051780:Sterol Regulatory Element Binding Protein 1; D058570:TOR Serine-Threonine Kinases; C497387:SREBF1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546842:MTOR protein, human