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Signal transducer and activator of transcription 3 pathway mediates genipin‐induced apoptosis in U266 multiple myeloma cells
Author(s) -
Lee Jang Choon,
Ahn Kwang Seok,
Jeong SooJin,
Jung Ji Hoon,
Kwon TaeRin,
Rhee YunHee,
Kim SunHee,
Kim SiYoung,
Yoon HwiJoong,
Zhu Shudong,
Chen ChangYan,
Kim SungHoon
Publication year - 2011
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.23077
Subject(s) - survivin , genipin , stat3 , cancer research , chemistry , cyclin d1 , stat protein , apoptosis , microbiology and biotechnology , biology , signal transduction , cell cycle , biochemistry , chitosan
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. J. Cell. Biochem. 112: 1552–1562, 2011. © 2011 Wiley‐Liss, Inc.