Abstract
Cytoskeletal rearrangement is required for migration and invasion, which are the key steps of cancer metastasis. Ezrin and integrin co-ordinate these processes by regulating cellular adhesion and cytoskeletal polymerization-depolymerization. It is also well established that chemokine-chemokine receptor axis plays a crucial role in regulating cancer cell migration and invasion. In this study, we show involvement of CXC chemokine receptor 6 (CXCR6) and its only natural ligand CXCL16 in pathobiology of prostate cancer (PCa). CXCR6 is highly expressed in PCa tissues and cell lines (LNCaP and PC3), relative to normal tissue and cells. CXCR6 expression in PCa tissues correlated with higher Gleason score. Similarly, aggressive PCa cells (PC3) show high CXCR6 compared to less aggressive LNCaP. Besides, PC3 cells show higher MMPs expression compared to LNCaP cells following CXCL16 stimulation. Intriguingly, CXCR6-CXCL16 interaction in PCa cells promotes Ezrin activation, αvβ3 integrin clustering and capping at the leading edge in FAK/PI3K/PKC dependent manner, thereby modifying cellular adhesion as well as motility. Together these results demonstrate that CXCL16 stimulation changes cytoskeletal dynamics resulting in enhanced migration, invasion and adhesion to endothelial cells, ultimately enabling PCa cells to achieve their metastatic goal.
Highlights
Tumor cells migrate to distant sites in response to chemokines via interaction with corresponding chemokine receptors [1,2,3,4,5]
Using tissue microarrays we found that expression of CXC chemokine receptor 6 (CXCR6) was higher in prostate cancer (PCa) tissue than normal adjacent
CXCR6 transcripts in both PCa cell lines were significantly higher than RWPE1
Summary
Tumor cells migrate to distant sites in response to chemokines via interaction with corresponding chemokine receptors [1,2,3,4,5]. Apart from cellular migration, this interaction provides an intracellular scaffold for the formation of specialized membrane domains that facilitate signal transduction through a number of growth factor receptor, including androgen receptor, and adhesion molecules that are important for tumor development and progression [11]. Cell adhesion to the extracellular matrix (ECM) involves the coordinated assembly and disassembly of integrins into complexes called focal adhesions. In these complexes, the internal tails of integrin β-subunits are typically linked to the actin cytoskeleton via cytoplasmic proteins, involved in scaffolding, adaptor, regulatory and mechano-transduction functions [14, 15]. We have provided the evidence that CXCR6-
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