The CXCL8-CXCR1/2 pathways in cancer

Abstract

Persistent infection or chronic inflammation contributes significantly to tumourigenesis and tumour progression. C-X-C motif ligand 8 (CXCL8) is a chemokine that acts as an important multifunctional cytokine to modulate tumour proliferation, invasion and migration in an autocrine or paracrine manner. Studies have suggested that CXCL8 and its cognate receptors, C-X-C chemokine receptor 1 (CXCR1) and C-X-C chemokine receptor 2 (CXCR2), mediate the initiation and development of various cancers including breast cancer, prostate cancer, lung cancer, colorectal carcinoma and melanoma. CXCL8 also integrates with multiple intracellular signalling pathways to produce coordinated effects. Neovascularisation, which provides a basis for fostering tumour growth and metastasis, is now recognised as a critical function of CXCL8 in the tumour microenvironment. In this review, we summarize the biological functions and clinical significance of the CXCL8 signalling axis in cancer. We also propose that CXCL8 may be a potential therapeutic target for cancer treatment.

Keywords: Angiogenesis; CXCL8; CXCR1; CXCR2; Cancer; Metastasis.

Fig. 1.

PyMOL Molecular Graphics System was used to present above structures. (A, B). Corresponding transmembrane regions within CXCR1 tertiary structure. Regions marked in different colours with arrows showed its seven transmembrane domains. Simulation of tertiary structure was constructed using PDB lefiof 2LNL produced by Park et al. [17]. (C, D). Corresponding transmembrane regions within CXCR2 tertiary structure. Regions marked in different colours with arrows showed its seven transmembrane domains. The amino acid sequence of CXCR2, NCBI RefSeq NP_0015481, were used to model CXCR2 tertiary structure in Swiss Model [155]. (E, F). Interaction model between CXCL8-dimer and CXCR1 N-terminal. Simulation of tertiary structure was constructed using PDB le of 1ILP produced by Skeltonfiet al. [16].

Fig. 2.

The diagram summarizing the major signalling pathways of CXCL8 in cancers. CXCL8 chemoattractant myeloid-derived suppressor cells (MDSCs) and tumour-associated neutrophils (TAN) to tumour microenvironment which are associated with immune suppression. At the celluar level, CXCL8 binds to G protein-coupled receptors (GPCRs), namely CXCR1 or CXCR2, leading to the activation of G protein. Heterotrimeric Ga and bg subunits stimulate the main effectors PLC and PI3K to induce phosphorylation of PKC and Akt, respectively. The two signalling pathways have been reported to activate respective transcription factors associated to survival, angiogenesis and migration of tumour cells. In addition, CXCL8 activates non-receptor tyrosine kinases (e.g., Src and FAK) and members of the RhoGTPase family, which promote cell proliferation, survival, motility and invasion. Activated Raf-1/MAP/Erk signalling cascade contributes to cell proliferation and survival. Dashed arrows, uncon rmed pathways involved in CXCL8 signalling axis.