TY - JOUR
T1 - Prostate cancer cells hyper-activate CXCR6 signaling by cleaving CXCL16 to overcome effect of docetaxel
AU - Kapur, Neeraj
AU - Mir, Hina
AU - Sonpavde, Guru P.
AU - Jain, Sanjay
AU - Bae, Sejong
AU - Lillard, James W.
AU - Singh, Shailesh
N1 - 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
UR - http://www.scopus.com/inward/record.url?scp=85064171418&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064171418&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2019.04.001
DO - 10.1016/j.canlet.2019.04.001
M3 - Article
C2 - 30974114
AN - SCOPUS:85064171418
SN - 0304-3835
VL - 454
SP - 1
EP - 13
JO - Cancer Letters
JF - Cancer Letters
ER -