title: Brassinin inhibits STAT3 signaling pathway through modulation of PIAS-3 and SOCS-3 expression and sensitizes human lung cancer xenograft in nude mice to paclitaxel.
abstract: Persistent phosphorylation of signal transducers and activators of transcription 3 (STAT3) is frequently observed in tumor cells. We found that brassinin (BSN) suppressed both constitutive and IL-6-inducible STAT3 activation in lung cancer cells. Moreover, BSN induced PIAS-3 protein and mRNA, whereas the expression of SOCS-3 was reduced. Knockdown of PIAS-3 by small interfering RNA prevented inhibition of STAT3 and cytotoxicity by BSN. Overexpression of SOCS-3 in BSN-treated cells increased STAT3 phosphorylation and cell viability. BSN down-regulated STAT3-regulated gene products, inhibited proliferation, invasion, as well as induced apoptosis. Most importantly, when administered intraperitoneally, combination of BSN and paclitaxel significantly decreased the tumor development in a xenograft lung cancer mouse model associated with down-modulation of phospho-STAT3, Ki-67 and CD31. We suggest that BSN inhibits STAT3 signaling through modulation of PIAS-3 and SOCS-3, thereby attenuating tumor growth and increasing sensitivity to paclitaxel.
authors: College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul, Republic of Korea.
authors: Jong Hyun
authors: JH
authors: Lee
authors: College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul, Republic of Korea.
authors: Chulwon
authors: C
authors: Kim
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Gautam
authors: G
authors: Sethi
authors: College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul, Republic of Korea.
authors: Kwang Seok
authors: KS
authors: Ahn
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020014:K562 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D011897:Random Allocation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D013859:Thiocarbamates / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000094162:Phytoalexins
chemical_list: D007211:Indoles; D018832:Molecular Chaperones; D017239:Paclitaxel; D050828:Protein Inhibitors of Activated STAT; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013859:Thiocarbamates; C484745:PIAS3 protein, human; C106644:SOCS3 protein, human; C494086:STAT3 protein, human; C089020:brassinin; D000094162:Phytoalexins
keywords: PIAS-3; SOCS-3; STAT3; apoptosis; brassinin