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

Yu Yu; Stephanie Gaillard; Jude M Phillip; Tai-Chung Huang; Sneha M Pinto; Nayara G Tessarollo; Zhen Zhang; Akhilesh Pandey; Denis Wirtz; Ayse Ayhan; Ben Davidson; Tian-Li Wang; Ie-Ming Shih

doi:10.1016/j.ccell.2015.05.009

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

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

Authors

Yu Yu¹, Stephanie Gaillard¹, Jude M Phillip², Tai-Chung Huang³, Sneha M Pinto³, Nayara G Tessarollo⁴, Zhen Zhang¹, Akhilesh Pandey⁵, Denis Wirtz⁶, Ayse Ayhan⁷, Ben Davidson⁸, Tian-Li Wang⁹, Ie-Ming Shih¹⁰

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects*
Drug Synergism
Female
Gene Knockdown Techniques
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Microtubule-Associated Proteins / metabolism
Microtubules / drug effects*
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
Oxazines / administration & dosage*
Oxazines / pharmacology
Paclitaxel / administration & dosage*
Paclitaxel / pharmacology
Phosphorylation / drug effects
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism
Pyridines / administration & dosage*
Pyridines / pharmacology
Syk Kinase
Tubulin / metabolism
Up-Regulation
Xenograft Model Antitumor Assays

Substances

Intracellular Signaling Peptides and Proteins
Microtubule-Associated Proteins
N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
Oxazines
Pyridines
Tubulin
Protein-Tyrosine Kinases
SYK protein, human
Syk Kinase
Paclitaxel

Abstract

Publication types

MeSH terms

Substances

Grants and funding