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

Prostate cancer cells hyper-activate CXCR6 signaling by cleaving CXCL16 to overcome effect of... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Letters Elsevier

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

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Publisher
Elsevier
Copyright
Copyright © 2019 Elsevier Ltd
ISSN
0304-3835
D.O.I.
10.1016/j.canlet.2019.04.001
Publisher site
See Article on Publisher Site

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.

Journal

Cancer LettersElsevier

Published: Jul 10, 2019

References

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