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: Jong Hyun Lee, Chulwon Kim, Gautam Sethi, Kwang Seok Ahn
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 8 Pg. 6386-405 (Mar 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25788267 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Indoles
• Molecular Chaperones
• PIAS3 protein, human
• Protein Inhibitors of Activated STAT
• SOCS3 protein, human
• STAT3 Transcription Factor
• STAT3 protein, human
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• Thiocarbamates
• brassinin
• Paclitaxel

Topics

• 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
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (metabolism)
• Thiocarbamates (pharmacology)
• Transfection
• Xenograft Model Antitumor Assays