title: CXCR1/2 antagonism with CXCL8/Interleukin-8 analogue CXCL8(3-72)K11R/G31P restricts lung cancer growth by inhibiting tumor cell proliferation and suppressing angiogenesis.
abstract: CXCR1 and CXCR2 together with cognate chemokines are significantly upregulated in a number of cancers, where they act as key regulators of tumor cell proliferation, metastasis, and angiogenesis. We have previously reported a mutant protein of CXCL8/Interleukin-8, CXCL8(3-72)K11R/G31P (G31P), which can act as a selective antagonist towards CXCR1/2 with therapeutic efficacy in both inflammatory diseases and malignancies. In this study, we investigated the effect of this ELR-CXC chemokine antagonist G31P on human non-small cell lung cancer cells and lung tumor progression in an orthotopic xenograft model. We report increased mRNA levels of CXCR1 and CXCR2 in human lung cancer tissues compared to normal counterparts. Expression levels of CXCR1/2 cognate ligands was determined by ELISA. CXCR1/2 receptor antagonism via G31P leads to decreased H460 and A549 cell proliferation and migration in a dose-dependent manner. G31P also enhanced apoptosis in lung cancer cells as determined by elevated levels of cleaved PARP, Caspase-8, and Bax, together with a reduced expression of the anti-apoptotic protein Bcl-2. In an in vivo orthotopic xenograft mouse model of human lung cancer, G31P treatment suppressed tumor growth, metastasis, and angiogenesis. At the molecular level, G31P treatment was correlated with decreased expression of VEGF and NFÐºB-p65, in addition to reduced phosphorylation of ERK1/2 and AKT. Our results suggest that G31P blockage of CXCR1 and CXCR2 can inhibit human lung cancer cell growth and metastasis, which offers potential therapeutic opportunities.
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.|Department of Immunology, Dalian Medical University, Dalian, China.
authors.forename: Muhammad Noman
authors.initials: MN
authors.lastname: Khan
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Yingqiu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jilin Medical College, Jilin, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Luan
authors.affiliation: Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Jya-Wei
authors.initials: JW
authors.lastname: Cheng
authors.affiliation: The Division of Respirology, Critical Care and Sleep Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Gordon
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Han
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C000604253:CXCL8(3-72)K11R,G31P, human; D016209:Interleukin-8; D008024:Ligands; D010446:Peptide Fragments; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B
keywords: CXCR antagonist; ELR-CXC chemokine; G31P; lung cancer