Format

Send to

Choose Destination
Cancer Cell. 2015 Jul 13;28(1):82-96. doi: 10.1016/j.ccell.2015.05.009. Epub 2015 Jun 18.

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

Author information

1
Department of Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
2
Department of Chemical and Biomolecular Engineering, Physical Sciences-Oncology Center, and Institute for NanoBioTechology, Johns Hopkins University, Baltimore, MD 21218, USA.
3
Department of Biological Chemistry and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
4
Department of Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA; Biotechnology Program/Renorbio, Health Science Center, Federal University of Espirito Santo, Vitória 29075-910, Brazil.
5
Department of Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA; Department of Biological Chemistry and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
6
Department of Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA; Department of Chemical and Biomolecular Engineering, Physical Sciences-Oncology Center, and Institute for NanoBioTechology, Johns Hopkins University, Baltimore, MD 21218, USA.
7
Department of Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA; Department of Pathology, Seirei Mikatahara Hospital and Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
8
Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, 0310 Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway.
9
Department of Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA. Electronic address: tlw@jhmi.edu.
10
Department of Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA; Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA. Electronic address: ishih@jhmi.edu.

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.

PMID:
26096845
PMCID:
PMC5257279
DOI:
10.1016/j.ccell.2015.05.009
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center