title: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.forename: Yanning
authors.initials: Y
authors.lastname: Wu
authors.forename: Yuning
authors.initials: Y
authors.lastname: Hou
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Guan
authors.forename: Marcello P
authors.initials: MP
authors.lastname: Castelvetere
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Oblak
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Filtz
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
authors.forename: Xuequn
authors.initials: X
authors.lastname: Chen
authors.forename: Bhanu P
authors.initials: BP
authors.lastname: Jena
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
references.citation: J Exp Med. 2005 Oct 3;202(7):975-86
references.pmid: 16203867
references.citation: Cancer Res. 2008 Dec 1;68(23):9754-62
references.pmid: 19047154
references.citation: J Biol Chem. 1996 Aug 30;271(35):21187-92
references.pmid: 8702889
references.citation: Cancer. 2002 Sep 15;95(6):1206-14
references.pmid: 12216086
references.citation: PLoS One. 2012;7(7):e40420
references.pmid: 22815748
references.citation: Cancer Immunol Immunother. 1998 Sep;47(1):47-57
references.pmid: 9755878
references.citation: Pancreas. 2000 Jul;21(1):52-6
references.pmid: 10881932
references.citation: Cancer Lett. 2010 Jun 28;292(2):246-53
references.pmid: 20089353
references.citation: Clin Cancer Res. 1999 Nov;5(11):3711-21
references.pmid: 10589791
references.citation: Cytokine Growth Factor Rev. 2006 Jun;17(3):147-56
references.pmid: 16516532
references.citation: Int J Cancer. 2009 Sep 1;125(5):1027-37
references.pmid: 19431209
references.citation: Int J Oncol. 2003 Apr;22(4):765-71
references.pmid: 12632066
references.citation: J Clin Invest. 1999 Mar;103(6):767-72
references.pmid: 10079096
references.citation: J Biol Chem. 2000 Jun 2;275(22):16632-7
references.pmid: 10748023
references.citation: Integr Biol (Camb). 2010 Apr;2(4):161-77
references.pmid: 20473396
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):342-6
references.pmid: 12502786
references.citation: CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
references.pmid: 22237781
references.citation: Physiol Genomics. 2010 Nov 15;42A(3):200-10
references.pmid: 20736413
references.citation: Int J Cancer. 2009 Feb 15;124(4):853-61
references.pmid: 19035451
references.citation: Cancer Lett. 2006 Sep 28;241(2):221-7
references.pmid: 16458421
references.citation: J Biol Chem. 2012 Feb 17;287(8):5744-55
references.pmid: 22203670
references.citation: J Biol Chem. 1993 Feb 15;268(5):3704-9
references.pmid: 8381437
references.citation: Cancer Res. 2005 Apr 1;65(7):2738-45
references.pmid: 15805273
references.citation: Cancer Sci. 2008 Apr;99(4):733-7
references.pmid: 18307536
references.citation: Cancer Lett. 2012 Mar 28;316(2):139-50
references.pmid: 22075379
references.citation: Curr Pharm Des. 2011;17(21):2221-38
references.pmid: 21777178
references.citation: J Biol Chem. 2008 Nov 7;283(45):30868-78
references.pmid: 18755694
references.citation: Cytokine. 2010 Feb;49(2):134-40
references.pmid: 20005738
references.citation: Annu Rev Biochem. 2001;70:281-312
references.pmid: 11395409
references.citation: Mol Pharmacol. 2006 Sep;70(3):860-8
references.pmid: 16763092
references.citation: J Vis Exp. 2012 Aug 13;(66):
references.pmid: 22907480
references.citation: Science. 2001 Jul 6;293(5527):98-101
references.pmid: 11441182
references.citation: Cell. 2007 Nov 30;131(5):940-51
references.pmid: 18045536
references.citation: Biochem Biophys Res Commun. 2001 Oct 19;288(1):1-7
references.pmid: 11594744
references.citation: Cell Signal. 2010 Jul;22(7):1153-61
references.pmid: 20227493
references.citation: Adv Enzyme Regul. 2011;51(1):138-51
references.pmid: 21035486
references.citation: Clin Cancer Res. 2008 Nov 1;14(21):6735-41
references.pmid: 18980965
references.citation: PLoS One. 2010 Jun 28;5(6):e11340
references.pmid: 20596532
references.citation: J Biol Chem. 2005 Apr 1;280(13):12467-73
references.pmid: 15632121
references.citation: Int J Cancer. 2004 Jan 10;108(2):181-8
references.pmid: 14639600
references.citation: Am J Physiol Regul Integr Comp Physiol. 2002 Jul;283(1):R7-28
references.pmid: 12069927
references.citation: J Biol Chem. 1994 Oct 14;269(41):25335-8
references.pmid: 7929227
references.citation: Pancreatology. 2008;8(4-5):488-97
references.pmid: 18765953
references.citation: Am J Pathol. 2011 Mar;178(3):1340-9
references.pmid: 21356384