title: Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules.
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.
authors.affiliation: Department of Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gaillard
authors.affiliation: Department of Chemical and Biomolecular Engineering, Physical Sciences-Oncology Center, and Institute for NanoBioTechology, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Jude M
authors.initials: JM
authors.lastname: Phillip
authors.affiliation: Department of Biological Chemistry and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Tai-Chung
authors.initials: TC
authors.lastname: Huang
authors.affiliation: Department of Biological Chemistry and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Sneha M
authors.initials: SM
authors.lastname: Pinto
authors.affiliation: 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.
authors.forename: Nayara G
authors.initials: NG
authors.lastname: Tessarollo
authors.affiliation: Department of Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Pandey
authors.affiliation: 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.
authors.forename: Denis
authors.initials: D
authors.lastname: Wirtz
authors.affiliation: 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.
authors.forename: Ayse
authors.initials: A
authors.lastname: Ayhan
authors.affiliation: 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.
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
authors.affiliation: Department of Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA. Electronic address: tlw@jhmi.edu.
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010078:Oxazines / Q000008:administration & dosage* / Q000494:pharmacology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D000072377:Syk Kinase; D014404:Tubulin / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D011725:Pyridines; D014404:Tubulin; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D017239:Paclitaxel