title: P27/Kip1 is responsible for magnolol-induced U373 apoptosis in vitro and in vivo.
abstract: Previously, we demonstrated that magnolol, a hydroxylated biphenyl compound isolated from the bark of Magnolia officinalis, at low concentrations (3-10 μM) exerted an antiproliferation effect in colon cancer, hepatoma, and glioblastoma (U373) cell lines through upregulation of the p21/Cip1 protein. Magnolol at a higher concentration of 100 μM, however, induced apoptosis and upregulated p27/Kip1 expression in U373. In the present study, we further studied whether the increased p27/Kip1 expression contributes to the magnolol-induced apoptosis in U373. Our data show that knock-down of p27/Kip1 expression significantly suppressed the magnolol-induced apoptosis, suggesting that p27/Kip1 might play an important role in the regulation of magnolol-induced apoptosis. This notion was further supported by demonstrating that magnolol induced an increase of the caspase activity in U373 in vitro and in vivo, and these effects were abolished by pretransfection of the cell with p27/Kip1 siRNA. To delineate the possible signaling pathways involved in the magnolol-induced increases of p27/Kip1 expression and apoptosis, we found that magnolol (100 μM) increased the levels of phosphorylated cSrc (p-cSrc), p-ERK, p-p38 MAP kinase (p-p38 MAPK), and p-AKT but not p-JNK in U373. Moreover, pretreatment of U373 with a cSrc inhibitor (PP2), a PI3K inhibitor (LY294002), an ERK inhibitor (PD98059), or a p38 MAPK inhibitor (SB203580) but not a JNK inhibitor (SP600125) significantly reduced the magnolol-induced increases of p27/Kip1 protein levels and apoptosis. Taken together, our data suggest that magnolol at a higher concentration of 100 μM induced apopotosis in U373 cells through cSrc-mediated upregulation of p27/Kip1.
authors: Graduate Institutes of Medical Sciences, College of Medicine, ‡Department of Physiology, School of Medicine, College of Medicine, and §Cancer Research Center, Taipei Medical University , Taipei 110, Taiwan.
authors: Li-Ching
authors: LC
authors: Chen
authors: Wen-Sen
authors: WS
authors: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D031566:Magnolia / Q000737:chemistry*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010936:Plant Extracts / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001713:Biphenyl Compounds; D017705:Lignans; D010936:Plant Extracts; C005498:magnolol; D050760:Cyclin-Dependent Kinase Inhibitor p27