Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Yu, Y; Gaillard, S; Phillip, JM; Huang, T-C; Pinto, SM; Tessarollo, NG; Zhang, Z; Pandey, A; Wirtz, D; Ayhan, A; Davidson, B; Wang, T-L; Shih, I-M

Published Date

  • July 13, 2015

Published In

Volume / Issue

  • 28 / 1

Start / End Page

  • 82 - 96

PubMed ID

  • 26096845

Pubmed Central ID

  • 26096845

Electronic International Standard Serial Number (EISSN)

  • 1878-3686

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2015.05.009

Language

  • eng

Conference Location

  • United States