Cancer Cell
Volume 28, Issue 1, 13 July 2015, Pages 82-96
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Article
Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules

https://doi.org/10.1016/j.ccell.2015.05.009Get rights and content
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Highlights

  • SYK is overexpressed in recurrent post-chemotherapy ovarian cancers

  • Inhibition of SYK synergistically enhances sensitivity to paclitaxel in tumor cells

  • SYK inhibition stabilizes microtubule in the presence of paclitaxel

  • Tubulin and MAPs are SYK substrates that may contribute to paclitaxel resistance

Summary

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.

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Present address: Department of Oncology, Duke Medical Center, Durham, NC 27710, USA