Journal
CANCER LETTERS
Volume 454, Issue -, Pages 1-13Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2019.04.001
Keywords
Docetaxel; Prostate cancer; CXCR6; CXCL16; ADAM10
Categories
Funding
- NCI [SC1 CA180212, UO1 CA179701, R21 CA169716, U54 CA118638]
- Morehouse School of Medicine - NIMHD [5U54MD007602]
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Molecular reprogramming in response to chemotherapeutics leads to poor therapeutic outcomes for prostate cancer (PCa). In this study, we demonstrated that CXCR6-CXCL16 aids 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-3 beta, NF-kappa B, 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 similar to 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.
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