CXCR2 Macromolecular Complex in Pancreatic Cancer: A Potential Therapeutic Target in Tumor Growth

Abstract

The signaling mediated by the chemokine receptor CXC chemokine receptor 2 (CXCR2) plays an important role in promoting the progression of many cancers, including pancreatic cancer, one of the most lethal human malignancies. CXCR2 possesses a consensus PSD-95/DlgA/ZO-1 (PDZ) motif at its carboxyl termini, which might interact with potential PDZ scaffold/adaptor proteins. We have previously reported that CXCR2 PDZ motif-mediated protein interaction is an important regulator for neutrophil functions. Here, using a series of biochemical assays, we demonstrate that CXCR2 is physically coupled to its downstream effector phospholipase C-β3 (PLC-β3) that is mediated by PDZ scaffold protein Na(+)/H(+) exchange regulatory factor 1 (NHERF1) into a macromolecular signaling complex both in vitro and in pancreatic cancer cells. We also observe that disrupting the CXCR2 complex, by gene delivery or peptide delivery of exogenous CXCR2 C-tail, significantly inhibits the biologic functions of pancreatic cancer cells (i.e., proliferation and invasion) in a PDZ motif-dependent manner. In addition, using a human pancreatic tumor xenograft model, we show that gene delivery of CXCR2 C-tail sequence (containing the PDZ motif) by adeno-associated virus type 2 viral vector potently suppresses human pancreatic tumor growth in immunodeficient mice. In summary, our results suggest the existence of a physical and functional coupling of CXCR2 and PLC-β3 mediated through NHERF1, forming a macromolecular complex that is critical for efficient and specific CXCR2 signaling in pancreatic cancer progression. Disrupting this CXCR2 complex could represent a novel and effective treatment strategy against pancreatic cancer.

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

“…The IL8-CXCR2 pathway has been shown to be important in the pathogenesis of solid tumors, and preclinical studies have demonstrated a role for this pathway in the breast cancer microenvironment. 22,27,28,30,45 Various small molecule CXCR2 inhibitors are being developed clinically, and one is being tested in a clinical trial in breast cancer. Our results demonstrate that this pathway is also functionally important for the viability of leukemic stem cell compartments in AML and MDS.…”

“…21 Blocking the IL8-CXCR1/CXCR2 axis has shown to be of therapeutic potential in a variety of solid tumors [27][28][29][30] ; however, there is little known of its role in hematologic malignancies. Our study reveals that IL8 is significantly overexpressed in AML and MDS LT-HSCs, ST-HSCs, and GMPs compared with healthy controls.…”

A critical role of CXCR2 PDZ-mediated interactions in endothelial progenitor cell homing and angiogenesis

“…Growth factor reduced Matrigel matrix, glutathione agarose beads and Transwell inserts were purchased from BD Bioscience. The human and murine CXCR2 C-tail peptides (biotin-conjugate at N-terminus): WT (biotin-FVGSSSGHTSTTL for human CXCR2 C-tail; and Biotin-FVSSSSANTSTTL for mouse CXCR2 C-tail) and PDZ motif deletion (ΔTTL) were synthesized by Genemed Synthesis, Inc. (San Antonio, TX), and used as reported before (Wu et al, 2012;Wang et al, 2013). SB225002 was purchased from Tocris Bioscience.…”

“…Of note, both human and murine CXCR2 possess a consensus PDZ motif at their carboxyl termini. We have recently reported that the PDZ motif (TTL) of CXCR2 is involved in the regulation of intracellular signaling and cellular functions in neutrophils (Wu et al, 2012) and pancreatic cancer cells (Wang et al, 2013). We showed that CXCR2 and its downstream signaling molecule PLC-β are clustered by a PDZ adaptor protein NHERF1 which scaffolds a CXCR2-PLC-β complex through PDZ-mediated interactions (Wu et al, 2012;Wang et al, 2013).…”

“…We have recently reported that the PDZ motif (TTL) of CXCR2 is involved in the regulation of intracellular signaling and cellular functions in neutrophils (Wu et al, 2012) and pancreatic cancer cells (Wang et al, 2013). We showed that CXCR2 and its downstream signaling molecule PLC-β are clustered by a PDZ adaptor protein NHERF1 which scaffolds a CXCR2-PLC-β complex through PDZ-mediated interactions (Wu et al, 2012;Wang et al, 2013). We also reported the crystal structure of the complex formation by X-ray crystallization, which provides the structural basis for CXCR2-mediated cellular functions in neutrophils and pancreatic cancer cells (Lu et al, 2013;Jiang et al, 2014).…”