title: Embelin suppresses STAT3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase PTEN.
abstract: Even though embelin, an inhibitor of the XIAP, is known to exhibit anti-inflammatory and anti-cancer activities, very little is known about its mechanism of action. Here, we investigated whether embelin mediates its effect through interference with the signal transducer and activator of transcription 3 (STAT3) pathway. We found that embelin inhibited constitutive STAT3 activation in a variety of human cancer cell lines such as U266, DU-145, and SCC4 cells. The suppression of STAT3 was mediated through inhibition of the activation of JAK2 and c-Src. Pervanadate treatment also reversed the embelin-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that embelin-induced the expression of the tyrosine phosphatase PTEN and deletion of the PTEN gene by small interfering RNA abolished the ability of embelin to inhibit STAT3 activation. Besides, embelin failed to suppress STAT3 activation in PTEN-null PC3 cells, thus indicating that the inhibitory effect of embelin on STAT3 is PTEN-dependent. Embelin down-regulated the expression of STAT3-regulated gene products; this correlated with the suppression of cell proliferation and invasion, and the induction of apoptosis through the activation of caspase-3. Overall, our results indicate that the anti-inflammatory and anti-cancer activities previously assigned to embelin may be mediated in part through the suppression of the STAT3 pathway.
authors.affiliation: College of Oriental Medicine, Institute of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Heo
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sung-Moo
authors.initials: SM
authors.lastname: Kim
authors.forename: Kyung-Ran
authors.initials: KR
authors.lastname: Park
authors.forename: Sang-Yoon
authors.initials: SY
authors.lastname: Park
authors.forename: Seong Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Dongwoo
authors.initials: D
authors.lastname: Nam
authors.forename: Hyeung-Jin
authors.initials: HJ
authors.lastname: Jang
authors.forename: Seok-Geun
authors.initials: SG
authors.lastname: Lee
authors.forename: Kyoo Seok
authors.initials: KS
authors.lastname: Ahn
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Bum Sang
authors.initials: BS
authors.lastname: Shim
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Choi
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D016227:Benzoquinones; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D011065:Poly(ADP-ribose) Polymerases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D017027:Protein Tyrosine Phosphatases; D053148:Caspase 3; C010945:embelin