RRR-alpha-tocopheryl succinate induction of DNA synthesis arrest of human MDA-MB-435 cells involves TGF-beta-independent activation of p21Waf1/Cip1.
RRR-alpha-tocopheryl succinate (vitamin E succinate, VES), a derivative of vitamin E, is a potent antitumor agent. Cellular events involved in VES-induced DNA synthesis arrest of human MDA-MB-435 breast cancer cells were studied. VES induces a dose- and time-dependent inhibition of DNA synthesis and a G0/G1 cell cycle arrest. VES induces expression of p21Waf1/Cip1 mRNA and protein, and antisense oligomers to p21 block VES-induced growth arrest. Evidence suggesting that VES modulates p21 expression in a transforming growth factor-beta (TGF-beta)-independent fashion includes failure of TGF-beta-neutralizing antibodies to block VES-induced DNA synthesis arrest or VES activation of a p21 promoter-regulated reporter gene; VES is not capable of inducing the translocation of green fluorescent protein-Smad2 into the nucleus and is not capable of stimulating a TGF-beta-dependent reporter gene, and VES induces growth inhibition and upregulates p21 mRNA levels in TGF-beta receptor-defective cells.
Yu
Weiping
W
School of Biological Sciences, University of Texas at Austin, Austin, TX 78712, USA.
Sanders
Bob G
BG
Kline
Kimberly
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D024505:Tocopherols; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology / Q000502:physiology; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D019384:Nucleic Acid Synthesis Inhibitors; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014810:Vitamin E; D008156:Luciferases; D024505:Tocopherols