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

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

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

111 Scopus citations

Abstract

Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies toovercome 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. Invitro, 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 invitro and invivo. 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.

Original language	English
Pages (from-to)	82-96
Number of pages	15
Journal	Cancer Cell
Volume	28
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2015.05.009
State	Published - 13 07 2015
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Inc..

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Yu, Y., Gaillard, S., Phillip, J. M., Huang, T. C., Pinto, S. M., Tessarollo, N. G., Zhang, Z., Pandey, A., Wirtz, D., Ayhan, A., Davidson, B., Wang, T. L., & Shih, I. M. (2015). Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules. Cancer Cell, 28(1), 82-96. https://doi.org/10.1016/j.ccell.2015.05.009

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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 toovercome 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. Invitro, 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 invitro and invivo. 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.",

author = "Yu Yu and Stephanie Gaillard and Phillip, {Jude M.} and Huang, {Tai Chung} and Pinto, {Sneha M.} and Tessarollo, {Nayara G.} and Zhen Zhang and Akhilesh Pandey and Denis Wirtz and Ayse Ayhan and Ben Davidson and Wang, {Tian Li} and Shih, {Ie Ming}",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc..",

year = "2015",

month = jul,

day = "13",

doi = "10.1016/j.ccell.2015.05.009",

language = "英语",

volume = "28",

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Yu, Y, Gaillard, S, Phillip, JM, Huang, TC, Pinto, SM, Tessarollo, NG, Zhang, Z, Pandey, A, Wirtz, D, Ayhan, A, Davidson, B, Wang, TL & Shih, IM 2015, 'Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules', Cancer Cell, vol. 28, no. 1, pp. 82-96. https://doi.org/10.1016/j.ccell.2015.05.009

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T1 - Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules

AU - Yu, Yu

AU - Gaillard, Stephanie

AU - Phillip, Jude M.

AU - Huang, Tai Chung

AU - Pinto, Sneha M.

AU - Tessarollo, Nayara G.

AU - Zhang, Zhen

AU - Pandey, Akhilesh

AU - Wirtz, Denis

AU - Ayhan, Ayse

AU - Davidson, Ben

AU - Wang, Tian Li

AU - Shih, Ie Ming

PY - 2015/7/13

Y1 - 2015/7/13

N2 - Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies toovercome 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. Invitro, 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 invitro and invivo. 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.

AB - Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies toovercome 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. Invitro, 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 invitro and invivo. 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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DO - 10.1016/j.ccell.2015.05.009

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AN - SCOPUS:84937441218

SN - 1535-6108

VL - 28

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JO - Cancer Cell

JF - Cancer Cell

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

Abstract

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