This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wang, J. Articles by Taichman, R. S. Search for Related Content PubMed PubMed Citation Articles by Wang, J. Articles by Taichman, R. S.

CXCR6 Induces Prostate Cancer Progression by the AKT/Mammalian Target of Rapamycin Signaling Pathway

¹ Shanghai Jiao-Tong University School of Medicine, Institute of Medical Sciences, Shanghai, P. R. China; ² Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry and ³ VA Medical Center and Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan; and ⁴ Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Requests for reprints: Jianhua Wang, Shanghai Jiao-Tong University School of Medicine, Institute of Medical Sciences, Shanghai, 200025, P. R. China. E-mail: jianhuaw2007{at}gmail.com or Russell S. Taichman, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109. Phone: 734-764-9952; Fax: 734-763-5503; E-mail: rtaich{at}umich.edu.

Key Words: CXCL16 • CXCR6 • prostate cancer

Previous studies show that the chemokine CXCL16 and its receptor CXCR6 are likely to contribute to prostate cancer (PCa). In this investigation, the role of the CXCR6 receptor in PCa was further explored. CXCR6 protein expression was examined using high-density tissue microarrays and immunohistochemistry. Expression of CXCR6 showed strong epithelial staining that correlated with Gleason score. In vitro and in vivo studies in PCa cell lines suggested that alterations in CXCR6 expression were associated with invasive activities and tumor growth. In addition, CXCR6 expression was able to regulate expression of the proangiogenic factors interleukin (IL)-8 or vascular endothelial growth factor (VEGF), which are likely to participate in the regulation of tumor angiogenesis. Finally, we found that CXCL16 signaling induced the activation of Akt, p70S6K, and eukaryotic initiation factor 4E binding protein 1 included in mammalian target of rapamycin (mTOR) pathways, which are located downstream of Akt. Furthermore, rapamycin not only drastically inhibited CXCL16-induced PCa cell invasion and growth but reduced secretion of IL-8 or VEGF levels and inhibited expression of other CXCR6 targets including CD44 and matrix metalloproteinase 3 in PCa cells. Together, our data shows for the first time that the CXCR6/AKT/mTOR pathway plays a central role in the development of PCa. Blocking the CXCR6/AKT/mTOR signaling pathway may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for PCa. [Cancer Res 2008;68(24):10367–76]