RRR-alpha-tocopheryl succinate induces MDA-MB-435 and MCF-7 human breast cancer cells to undergo differentiation.
RRR-alpha-Tocopheryl succinate (vitamin E succinate, VES) is a potent antitumor agent, inducing DNA synthesis arrest, differentiation, and apoptosis. Because little is known about VES-induced differentiation, studies reported here characterize VES effects on the differentiation status of human breast cancer cell lines and investigate possible molecular mechanisms involved. VES-induced differentiation of human MCF-7 and MDA-MB-435 breast cancer cells was characterized by morphological changes, induction of lipid droplets, induction of beta-casein mRNA expression, and down-regulation of Her2/neu protein. In contrast, VES treatment of normal human mammary epithelial cells, MCF-10A cells, and T-47D cells did not induce differentiation. Studies addressing mechanisms showed that neither antibody neutralization of the transforming growth factor-beta signaling pathway nor expression of a dominant-negative mutant of c-Jun N-terminal kinase blocked the ability of VES to induce differentiation; however, treatment of cells with PD 98059, a chemical inhibitor of mitogen-activated protein kinase kinase (MEK1/2), blocked the ability of VES to induce differentiation.
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School of Biological Sciences/C0900, University of Texas at Austin, Austin, Texas 78712, USA.
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Sanders
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Kline
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D000906:Antibodies / Q000378:metabolism; D015415:Biomarkers; D001943:Breast Neoplasms; D002364:Caseins / Q000235:genetics; D002454:Cell Differentiation; D019938:Cyclin D1 / Q000096:biosynthesis; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D007633:Keratins / Q000096:biosynthesis; D050356:Lipid Metabolism; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009500:Neutralization Tests; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D015398:Signal Transduction; D024505:Tocopherols; D015534:Trans-Activators; D014157:Transcription Factors / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D051176:beta Catenin
D000906:Antibodies; D015415:Biomarkers; D002364:Caseins; D019938:Cyclin D1; D003598:Cytoskeletal Proteins; D018799:Intercellular Adhesion Molecule-1; D048031:JNK Mitogen-Activated Protein Kinases; D007633:Keratins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D024505:Tocopherols; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014810:Vitamin E; D051176:beta Catenin; C495270:CTNNB1 protein, human