Journal Article

Targeting CXCR2 inhibits the progression of lung cancer and promotes therapeutic effect of cisplatin

Cheng, Yuan, Mo, Fei, Li, Qingfang, Chen, Siyuan, Wei, Xiawei, Wei, Yuquan, Han, Xuejiao, Shi, Houhui

2021

Overview

Background Drug-resistance and severe side effects of chemotherapeutic agents result in unsatisfied survival of patients with lung cancer. CXCLs/CXCR2 axis plays an important role in progression of cancer including lung cancer. However, the specific anti-cancer mechanism of targeting CXCR2 remains unclear. Methods Immunohistochemical analysis of CXCR2 was performed on the microarray of tumor tissues of clinical lung adenocarcinoma and lung squamous cell carcinoma patients. CCK8 test, TUNEL immunofluorescence staining, PI-Annexin V staining, β-galactosidase staining, and Western blot were used to verify the role of CXCR2 in vitro. Animal models of tail vein and subcutaneous injection were applied to investigate the therapeutic role of targeting CXCR2. Flow cytometry, qRT-PCR, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry analysis were performed for further mechanistic investigation. Results The expression of CXCR2 was elevated in both human lung cancer stroma and tumor cells, which was associated with patients’ prognosis. Inhibition of CXCR2 promoted apoptosis, senescence, epithelial-to-mesenchymal transition (EMT), and anti-proliferation of lung cancer cells. In vivo study showed that tumor-associated neutrophils (TANs) were significantly infiltrate into tumor tissues of mouse model, with up-regulated CXCLs/CXCR2 signaling and suppressive molecules, including Arg-1 and TGF-β. SB225002, a selective inhibitor of CXCR2 showed promising therapeutic effect, and significantly reduced infiltration of neutrophils and enhanced anti-tumor T cell activity via promoting CD8 + T cell activation. Meanwhile, blockade of CXCR2 could enhance therapeutic effect of cisplatin via regulation of neutrophils infiltration. Conclusions Our finds verify the therapeutic effects of targeting CXCR2 in lung cancer and uncover the potential mechanism for the increased sensitivity to chemotherapeutic agents by antagonists of CXCR2.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenocarcinoma / Analysis / Angiogenesis / Animal models / Annexin V / Antagonists / Apoptosis / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cancer therapies / Carboplatin / CD8 antigen / Cell activation / Cell growth / Cell proliferation / Chemokines / Chemotherapy / Cisplatin / CXCR2 / CXCR2 protein / Cytokines / Development and progression / Drug resistance / Enzyme-linked immunosorbent assay / Enzymes / FDA approval / Flow cytometry / Health aspects / Immunofluorescence / Immunohistochemistry / Infiltration / Kinases / Leukocytes (neutrophilic) / Ligands / Lung cancer / Lung carcinoma / Lymphocytes T / Medical prognosis / Mesenchyme / Metastases / Neutrophils / Oncology / Oncology, Experimental / Proteins / Radiation therapy / SB225002 / Senescence / Squamous cell carcinoma / Survival analysis / T cells / Transforming growth factors / Tumor cells / β-Galactosidase