Insulin‐like growth factor‐1 signaling is responsible for cathepsin G‐induced aggregation of breast cancer MCF‐7 cells

Abstract

Cathepsin G (CG), a neutrophil serine protease, induces cell migration and multicellular aggregation of human breast cancer MCF‐7 cells in a process that is dependent on E‐cadherin and CG enzymatic activity. While these tumor cell aggregates can cause tumor emboli that could represent intravascular growth and extravasation into the surrounding tissues, resulting in metastasis, the molecular mechanism underlying this process remains poorly characterized. In this study, we aimed to identify the signaling pathway that is triggered during CG‐mediated stimulation of cell aggregation. Screening of a library of compounds containing approximately 90 molecular‐targeting drugs revealed that this process was suppressed by the insulin‐like growth factor‐1 (IGF‐1) receptor (IGF‐1R)‐specific kinase inhibitor OSI‐906, as well as the multikinase inhibitors axitinib and sunitinib. Antibody array analysis, which is capable of detecting tyrosine phosphorylation of 49 distinct receptor tyrosine kinases, and the results of immunoprecipitation studies indicated that IGF‐1R is phosphorylated in response to CG treatment. Notably, IGF‐1R neutralization via treatment with a specific antibody or silencing of IGF‐1R expression through siRNA transfection suppressed cell aggregation. Furthermore, CG treatment of MCF‐7 cells resulted in increased release of IGF‐1 into the medium for 24 h, while antibody‐mediated IGF‐1 neutralization partially prevented CG‐induced cell aggregation. These results demonstrate that autocrine IGF‐1 signaling is partly responsible for the cell aggregation induced by CG.

Bioinformatics Analyses Indicate That Cathepsin G (CTSG) is a Potential Immune-Related Biomarker in Oral Squamous Cell Carcinoma (OSCC)

“…Most of them were proved to be related to various cancers. For example, CTSG could promote cell migration and multicellular aggregation in human breast cancer MCF-7 cells through depending on E-cadherin 24 and was an immunotherapeutic target in acute myeloid leukemia (AML). 25 Our study showed that CTSG could inhibit OSCC proliferation, migration, invasion, and the induction of EMT in vitro, which plays a key role in tumorigenesis and progression, and a higher CTSG expression level meant well-pleasing overall survival and early-stage tumor.…”

Tumor-Associated Neutrophils in Cancer: Going Pro

“…The high isoelectric points for CG (12) cause them to be easily caught in negatively charged traps such as neutrophil extracellular traps (NETs) [96]. In breast cancer, CG facilitated the E-cadherin-dependent aggregation of mammary carcinoma cells, MCF-7 [97], and it was through insulin-like growth factor-1 signaling [98]. Inhibition of CG resulted in less osteolysis in breast cancer, which indicated CG as a potential therapeutic target [99].…”

A TP53-based immune prognostic model for muscle-invasive bladder cancer

“…These four key genes are involved in various cancer-related immune processes. Cathepsin G (CTSG), an azurophil granule protease, can lead to breast cancer cell migration [ 28 , 29 ] and can enter tumor endosomes by binding to a cell surface receptor [ 30 ]. Previous studies have shown that CTSG degraded MHC I on the human glioblastoma cell surface of primary immune cells.…”