title: Janus activated kinase 2/signal transducer and activator of transcription 3 pathway mediates icariside II-induced apoptosis in U266 multiple myeloma cells.
abstract: Although the flavonoid icariside II exhibits anti-inflammatory and anti-cancer activities, its molecular targets/pathways in human multiple myeloma cells are poorly understood. To analyze the effects on signal transducer and activator of transcription 3 (STAT3) signaling and apoptosis, U266 multiple myeloma cells were treated with icariside II and performed Western blotting, electrophoretic mobility gel shift assay (EMSA), RT-PCR, proliferation assay, cell cycle analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Icariside II inhibited STAT3 activation and enhanced the expression of SHP-1 and PTEN through inhibiting Janus activated kinase 2 (JAK2) and c-Src. Icariside II down-regulated the expression of STAT3 target genes Bcl-2, Bcl-x(L), survivin, cyclin D(1), COX-2 and vascular endothelial growth factor (VEGF). Also, icariside II enhanced poly (ADP-ribose) polymerase (PARP) cleavage and caspase-3 activation. Pervanadate reversed the icariside II-mediated STAT3 inactivation and also blocked the cleavages of caspase-3 and PARP, suggesting involvement of STAT3 pathway in icariside II-induced apoptosis. Furthermore, icariside II enhanced the apoptotic effects of clinically used drugs thalidomide and bortezomib in U266 cells. Icariside II could be a potential therapeutic intervention agent alone or in combination with current drugs for multiple myeloma as a novel blocker of STAT3 signaling cascades at multiple levels, contributing to its anti-proliferative and anti-apoptosis.
authors.affiliation: Cancer Preventive Material, Development Research Center, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul, South Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Tae-Rin
authors.initials: TR
authors.lastname: Kwon
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jung
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Yun
authors.forename: Ihn
authors.initials: I
authors.lastname: Han
authors.forename: Seok-Geun
authors.initials: SG
authors.lastname: Lee
authors.forename: Dae Keun
authors.initials: DK
authors.lastname: Kim
authors.forename: Minkyung
authors.initials: M
authors.lastname: Kang
authors.forename: Chang-Yan
authors.initials: CY
authors.lastname: Chen
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013792:Thalidomide / Q000008:administration & dosage
chemical_list: D001897:Boronic Acids; D005419:Flavonoids; D011719:Pyrazines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C060988:baohuoside I; D013792:Thalidomide; D000069286:Bortezomib; C507924:JAK2 protein, human; D053614:Janus Kinase 2