title: Signal transducer and activator of transcription 3 pathway mediates genipin-induced apoptosis in U266 multiple myeloma cells.
abstract: It has drawn a lot of attention to target signal transducer and activator of transcription 3 (STAT3) as a potential strategy for cancer therapeutics. Using several myelogenous cell lines, the effect of genipin (an active compound of Gardenia fruit) on the STAT3 pathway and apoptosis was investigated. Genipin suppressed the constitutive STAT3 activation in U266 and U937 cells and stimulated Src homology 2 domain-containing phosphatase 1 (SHP-1), which dephosphorylates and inactivates STAT3. Specifically, genipin blocked STAT3 activation via repressing the activation of c-Src, but not Janus kinase 1 (JAK1). Genipin also downregulated the expression of STAT3 target genes including Bcl-2, Bcl-x(L) , Survivin, Cyclin D1, and VEGF. Conversely, protein tyrosine phosphatase inhibitor pervanadate blocked genipin induced STAT3 inactivation. Using DNA fragmentation or TUNEL assays, we demonstrated the apoptotic effect of genipin on U266, MM.1S, and U937 cells. Furthermore, genipin effectively potentiated the cytotoxic effect of chemotherapeutic agents, such as bortezomib, thalidomide, and paclitaxel in U266 cells. Our data suggest that through regulation of Src and SHP-1, genipin antagonizes STAT3 for the induction of apoptosis in myeloma cells.
authors.affiliation: College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Jang Choon
authors.initials: JC
authors.lastname: Lee
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jung
authors.forename: Tae-Rin
authors.initials: TR
authors.lastname: Kwon
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Rhee
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Si-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Hwi-Joong
authors.initials: HJ
authors.lastname: Yoon
authors.forename: Shudong
authors.initials: S
authors.lastname: Zhu
authors.forename: Chang-Yan
authors.initials: CY
authors.lastname: Chen
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D020287:In Situ Nick-End Labeling; D057889:Iridoid Glycosides; D039823:Iridoids; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D057889:Iridoid Glycosides; D039823:Iridoids; D011719:Pyrazines; D050796:STAT3 Transcription Factor; D000069286:Bortezomib; C007834:genipin