Prostate cancer cells hyper-activate CXCR6 signaling by cleaving CXCL16 to overcome effect of docetaxel

Neeraj Kapur; Hina Mir; Guru P. Sonpavde; Sanjay Jain; Sejong Bae; James W. Lillard; Shailesh Singh

doi:10.1016/j.canlet.2019.04.001

Prostate cancer cells hyper-activate CXCR6 signaling by cleaving CXCL16 to overcome effect of docetaxel

Neeraj Kapur, Hina Mir, Guru P. Sonpavde, Sanjay Jain, Sejong Bae, James W. Lillard, Shailesh Singh

Internal Medicine

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

18 Scopus citations

Abstract

Molecular reprogramming in response to chemotherapeutics leads to poor therapeutic outcomes for prostate cancer (PCa). In this study, we demonstrated that CXCR6-CXCL16 axis promotes DTX resistance and acts as a counter-defense mechanism. After CXCR6 activation, cell death in response to DTX was inhibited, and blocking of CXCR6 potentiated DTX cytotoxicity. Moreover, in response to DTX, PCa cells expressed higher CXCR6, CXCL16, and ADAM-10. Furthermore, ADAM-10-mediated release of CXCL16 hyper-activated CXCR6 signaling in response to DTX. Activation of CXCR6 resulted in increased GSK-3β, NF-κB, ERK1/2 phosphorylation, and survivin expression, which reduce DTX response. Finally, treatment of PCa cells with anti-CXCR6 monoclonal antibody synergistically or additively induced cell death with ∼1.5–4.5 fold reduction in the effective concentration of DTX. In sum, our data imply that co-targeting of CXCR6 would lead to therapeutic enhancement of DTX, leading to better clinical outcomes for PCa patients.

Original language	English
Pages (from-to)	1-13
Number of pages	13
Journal	Cancer Letters
Volume	454
DOIs	https://doi.org/10.1016/j.canlet.2019.04.001
State	Published - Jul 10 2019

Bibliographical note

Funding Information:
This study was supported in part by the funds ( SC1 CA180212 , UO1 CA179701 , R21 CA169716 and U54 CA118638 ) from NCI and Morehouse School of Medicine flow cytometry core supported by the NIMHD 5U54MD007602 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH . Authors would also like to acknowledge Don Hill, scientific editor of U54 partnership for editing this manuscript.

Funding Information:
This study was supported in part by the funds (SC1 CA180212, UO1 CA179701, R21 CA169716 and U54 CA118638) from NCI and Morehouse School of Medicine flow cytometry core supported by the NIMHD 5U54MD007602. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Authors would also like to acknowledge Don Hill, scientific editor of U54 partnership for editing this manuscript.

Publisher Copyright:
© 2019

Keywords

ADAM10
CXCL16
CXCR6
Docetaxel
Prostate cancer

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.canlet.2019.04.001

Cite this

@article{023ac016c0cc4d7f927d4922ee3ea164,

title = "Prostate cancer cells hyper-activate CXCR6 signaling by cleaving CXCL16 to overcome effect of docetaxel",

abstract = "Molecular reprogramming in response to chemotherapeutics leads to poor therapeutic outcomes for prostate cancer (PCa). In this study, we demonstrated that CXCR6-CXCL16 axis promotes DTX resistance and acts as a counter-defense mechanism. After CXCR6 activation, cell death in response to DTX was inhibited, and blocking of CXCR6 potentiated DTX cytotoxicity. Moreover, in response to DTX, PCa cells expressed higher CXCR6, CXCL16, and ADAM-10. Furthermore, ADAM-10-mediated release of CXCL16 hyper-activated CXCR6 signaling in response to DTX. Activation of CXCR6 resulted in increased GSK-3β, NF-κB, ERK1/2 phosphorylation, and survivin expression, which reduce DTX response. Finally, treatment of PCa cells with anti-CXCR6 monoclonal antibody synergistically or additively induced cell death with ∼1.5–4.5 fold reduction in the effective concentration of DTX. In sum, our data imply that co-targeting of CXCR6 would lead to therapeutic enhancement of DTX, leading to better clinical outcomes for PCa patients.",

keywords = "ADAM10, CXCL16, CXCR6, Docetaxel, Prostate cancer",

author = "Neeraj Kapur and Hina Mir and Sonpavde, {Guru P.} and Sanjay Jain and Sejong Bae and Lillard, {James W.} and Shailesh Singh",

note = "Funding Information: This study was supported in part by the funds ( SC1 CA180212 , UO1 CA179701 , R21 CA169716 and U54 CA118638 ) from NCI and Morehouse School of Medicine flow cytometry core supported by the NIMHD 5U54MD007602 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH . Authors would also like to acknowledge Don Hill, scientific editor of U54 partnership for editing this manuscript. Funding Information: This study was supported in part by the funds (SC1 CA180212, UO1 CA179701, R21 CA169716 and U54 CA118638) from NCI and Morehouse School of Medicine flow cytometry core supported by the NIMHD 5U54MD007602. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Authors would also like to acknowledge Don Hill, scientific editor of U54 partnership for editing this manuscript. Publisher Copyright: {\textcopyright} 2019",

year = "2019",

month = jul,

day = "10",

doi = "10.1016/j.canlet.2019.04.001",

language = "English",

volume = "454",

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AU - Kapur, Neeraj

AU - Mir, Hina

AU - Sonpavde, Guru P.

AU - Jain, Sanjay

AU - Bae, Sejong

AU - Lillard, James W.

AU - Singh, Shailesh

N1 - Funding Information: This study was supported in part by the funds ( SC1 CA180212 , UO1 CA179701 , R21 CA169716 and U54 CA118638 ) from NCI and Morehouse School of Medicine flow cytometry core supported by the NIMHD 5U54MD007602 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH . Authors would also like to acknowledge Don Hill, scientific editor of U54 partnership for editing this manuscript. Funding Information: This study was supported in part by the funds (SC1 CA180212, UO1 CA179701, R21 CA169716 and U54 CA118638) from NCI and Morehouse School of Medicine flow cytometry core supported by the NIMHD 5U54MD007602. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Authors would also like to acknowledge Don Hill, scientific editor of U54 partnership for editing this manuscript. Publisher Copyright: © 2019

PY - 2019/7/10

Y1 - 2019/7/10

N2 - Molecular reprogramming in response to chemotherapeutics leads to poor therapeutic outcomes for prostate cancer (PCa). In this study, we demonstrated that CXCR6-CXCL16 axis promotes DTX resistance and acts as a counter-defense mechanism. After CXCR6 activation, cell death in response to DTX was inhibited, and blocking of CXCR6 potentiated DTX cytotoxicity. Moreover, in response to DTX, PCa cells expressed higher CXCR6, CXCL16, and ADAM-10. Furthermore, ADAM-10-mediated release of CXCL16 hyper-activated CXCR6 signaling in response to DTX. Activation of CXCR6 resulted in increased GSK-3β, NF-κB, ERK1/2 phosphorylation, and survivin expression, which reduce DTX response. Finally, treatment of PCa cells with anti-CXCR6 monoclonal antibody synergistically or additively induced cell death with ∼1.5–4.5 fold reduction in the effective concentration of DTX. In sum, our data imply that co-targeting of CXCR6 would lead to therapeutic enhancement of DTX, leading to better clinical outcomes for PCa patients.

AB - Molecular reprogramming in response to chemotherapeutics leads to poor therapeutic outcomes for prostate cancer (PCa). In this study, we demonstrated that CXCR6-CXCL16 axis promotes DTX resistance and acts as a counter-defense mechanism. After CXCR6 activation, cell death in response to DTX was inhibited, and blocking of CXCR6 potentiated DTX cytotoxicity. Moreover, in response to DTX, PCa cells expressed higher CXCR6, CXCL16, and ADAM-10. Furthermore, ADAM-10-mediated release of CXCL16 hyper-activated CXCR6 signaling in response to DTX. Activation of CXCR6 resulted in increased GSK-3β, NF-κB, ERK1/2 phosphorylation, and survivin expression, which reduce DTX response. Finally, treatment of PCa cells with anti-CXCR6 monoclonal antibody synergistically or additively induced cell death with ∼1.5–4.5 fold reduction in the effective concentration of DTX. In sum, our data imply that co-targeting of CXCR6 would lead to therapeutic enhancement of DTX, leading to better clinical outcomes for PCa patients.

KW - ADAM10

KW - CXCL16

KW - CXCR6

KW - Docetaxel

KW - Prostate cancer

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SN - 0304-3835

VL - 454

SP - 1

EP - 13

JO - Cancer Letters

JF - Cancer Letters

ER -

Prostate cancer cells hyper-activate CXCR6 signaling by cleaving CXCL16 to overcome effect of docetaxel

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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