title: Bergamottin, a natural furanocoumarin obtained from grapefruit juice induces chemosensitization and apoptosis through the inhibition of STAT3 signaling pathway in tumor cells.
abstract: Persistent activation of signal transducers and activator of transcription 3 (STAT3) has been closely related to growth, survival, proliferation, metastasis, and angiogenesis of various cancer cells, and thus its inhibition can be considered a potential therapeutic strategy. In this study, we investigated the role of bergamottin (BGM) obtained from grapefruit juice in abrogating the constitutive STAT3 activation in multiple myeloma (MM) cells. This suppression was mediated through the inhibition of phosphorylation of Janus-activated kinase (JAK) 1/2 and c-Src. Pervanadate reversed the BGM induced down-regulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase (PTP). Furthermore, BGM induced the expression of the tyrosine phosphatase SHP-1, and gene silencing of the SHP-1 by small interfering RNA abolished the ability of BGM to inhibit STAT3 activation, suggesting a critical role for SHP-1 in the action of BGM. BGM also downregulated the expression of STAT3-regulated gene products such as COX-2, VEGF, cyclin D1, survivin, IAP-1, Bcl-2, and Bcl-xl in MM cells. This correlated with induction of substantial apoptosis as indicated by an increase in the sub-G1 cell population and caspase-3 induced PARP cleavage. Also, this agent significantly potentiated the apoptotic effects of bortezomib and thalidomide in MM cells. Overall, these results suggest that BGM is a novel blocker of STAT3 activation pathway thus may have a potential in therapy of MM and other cancers.
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, Korea.
authors.forename: Sung-Moo
authors.initials: SM
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, Korea.
authors.forename: Jong Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, and Cancer Science Institute of Singapore, National University of Singapore, Singapore 117597.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, Korea.
authors.forename: Chulwon
authors.initials: C
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, Korea.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Baek
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, Korea.
authors.forename: Dongwoo
authors.initials: D
authors.lastname: Nam
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, Korea.
authors.forename: Won-Seok
authors.initials: WS
authors.lastname: Chung
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, Korea.
authors.forename: Bum Sang
authors.initials: BS
authors.lastname: Shim
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, Korea. Electronic address: ksahn@khu.ac.kr.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D032083:Citrus paradisi / Q000737:chemistry; D011564:Furocoumarins / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation; D009101:Multiple Myeloma / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D011564:Furocoumarins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C068337:bergamottin
keywords: Apoptosis; Bergamottin; Multiple myeloma; SHP-1; STAT3