Abstract
Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies to overcome drug resistance would have significant clinical impact. We report that recurrent ovarian carcinomas after paclitaxel/carboplatin treatment have higher levels of spleen tyrosine kinase (SYK) and phospho-SYK. In vitro, paclitaxel-resistant cells expressed higher SYK, and the ratio of phospho-SYK/SYK positively associated with paclitaxel resistance in ovarian cancer cells. Inactivation of SYK by inhibitors or gene knockdown sensitized paclitaxel cytotoxicity in vitro and in vivo. Analysis of the phosphotyrosine proteome in paclitaxel-resistant tumor cells revealed that SYK phosphorylates tubulins and microtubule-associated proteins. Inhibition of SYK enhanced microtubule stability in paclitaxel-resistant tumor cells that were otherwise insensitive. Thus, targeting SYK pathway is a promising strategy to enhance paclitaxel response.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Drug Resistance, Neoplasm / drug effects*
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Drug Synergism
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Female
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Gene Knockdown Techniques
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Microtubule-Associated Proteins / metabolism
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Microtubules / drug effects*
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Oxazines / administration & dosage*
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Oxazines / pharmacology
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Paclitaxel / administration & dosage*
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Paclitaxel / pharmacology
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Phosphorylation / drug effects
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Pyridines / administration & dosage*
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Pyridines / pharmacology
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Syk Kinase
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Tubulin / metabolism
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Up-Regulation
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Xenograft Model Antitumor Assays
Substances
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Intracellular Signaling Peptides and Proteins
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Microtubule-Associated Proteins
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N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
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Oxazines
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Pyridines
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Tubulin
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Paclitaxel