title: The flavonoid resveratrol suppresses growth of human malignant pleural             mesothelioma cells through direct inhibition of specificity protein 1.
abstract: Resveratrol (Res), from the skin of red grapes, induces apoptosis in some malignant cells, but there are no reports on the apoptotic effect of Res on human malignant pleural mesothelioma. We found that Res interacts with specificity protein 1 (Sp1). The IC50 for Res was 17 µM in MSTO-211H cells. Cell viability was decreased and apoptotic cell death was increased by Res (0-60 µM). Res increased the Sub-G1 population in MSTO-211H cells and significantly suppressed Sp1 protein levels, but not Sp1 mRNA levels. Res modulated the expression of Sp1 regulatory proteins including p21, p27, cyclin D1, Mcl-1 and survivin in mesothelioma cells. After treatment with Res, apoptosis signaling cascades were activated by the activation of Bid, Bim, caspase-3 and PARP, upregulation of Bax and downregulation of Bcl-xL. Res (20 mg/kg daily for 4 weeks) effectively suppressed tumor growth in vivo in BALB/c athymic (nu+/nu+) mice injected with MSTO-211H cells, an effect that was mediated by inhibition of Sp1 expression and induction of apoptotic cell death. Our results strongly suggest that Sp1 is a novel molecular target of Res in human malignant pleural mesothelioma.
authors.affiliation: Department of Biochemistry, College of Medicine, Soonchunhyang                     University, Cheonan 330-090, Republic of Korea.
authors.forename: Kyung-Ae
authors.initials: KA
authors.lastname: Lee
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Jung Ok
authors.initials: JO
authors.lastname: Ban
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Sang-Han
authors.initials: SH
authors.lastname: Lee
authors.forename: Moon-Kyun
authors.initials: MK
authors.lastname: Cho
authors.forename: Hae-Seon
authors.initials: HS
authors.lastname: Nam
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D008565:Membrane Proteins / Q000096:biosynthesis; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013267:Stilbenes / Q000378:metabolism* / Q000494:pharmacology*; D000077022:Survivin; D014183:Transplantation, Heterologous; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C107489:BIRC5 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051034:Inhibitor of Apoptosis Proteins; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D013267:Stilbenes; D000077022:Survivin; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D000077185:Resveratrol