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

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, wherea...

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Bibliographic Details
Published in:Oncotarget 2015-03, Vol.6 (8), p.6386-6405
Main Authors: Lee, Jong Hyun, Kim, Chulwon, Sethi, Gautam, Ahn, Kwang Seok
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Cell Proliferation - drug effects
Humans
Indoles - pharmacology
K562 Cells
Male
Mice
Mice, Nude
Molecular Chaperones - metabolism
Paclitaxel - pharmacology
Protein Inhibitors of Activated STAT - metabolism
Random Allocation
Research Paper
Signal Transduction - drug effects
STAT3 Transcription Factor - antagonists & inhibitors
STAT3 Transcription Factor - metabolism
Suppressor of Cytokine Signaling 3 Protein
Suppressor of Cytokine Signaling Proteins - metabolism
Thiocarbamates - pharmacology
Transfection
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.3443