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.

Muhammad Noman Khan,Xuelin Luan,John R Gordon,Bing Wang,Han Liu,Jing Wei,Fang Li,Jya-Wei Cheng,Yingqiu Zhang,Qiang Li

doi:10.18632/oncotarget.4066

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.

Highlights

Lung cancer is a leading cause of death in the world
This study focused on the impact of CXCR1 and CXCR2 antagonism by G31P on proliferation, migration, survival and growth of nonsmall cell carcinoma cells and tumors in vitro and in vivo, the latter as determined in a xenograft mouse model
Our results clearly indicate that G31P has inhibitory effects on lung cancer growth, metastasis, and angiogenesis, at least in part through its effects on the MAPK and AKT signaling pathways

Summary

Introduction

Lung cancer is a leading cause of death in the world. The mortality rate due to lung cancer has increased over the past 3 decades, surpassing liver cancer as the leading cause of death due to malignant tumors in China [1, 2]. Recent targeted therapy approaches against Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Receptor Tyrosine Kinase (ALK) have shown promising results and been approved for clinical use. This group only accounts for a small proportion of lung cancer, and the remaining majority still lacks a druggable target till

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