Abstract
Calgranulin B is a small, calcium-binding protein expressed in neutrophils that is secreted into the tumor microenvironment in cancer cases. We previously showed that calgranulin B levels are increased in the stools of colorectal cancer patients. In patient tumor tissues, calgranulin B protein levels correlated with the presence of stromal inflammatory cells surrounding tumor cells, and calgranulin B promoter methylation was observed in both paired human tissues and colon cancer cell lines. Cell lines did not express calgranulin B, but in vitro studies showed that colon cancer cells internalized extracellular calgranulin B, while other types of cancer cells did not. Calgranulin B internalization led to reduced cell proliferation and increased apoptotic cell death. AKT and ERK signals were also increased after calgranulin B treatment, as were p53, β-catenin, E-cadherin and cleaved caspase-3 levels. Additionally, a human protein microarray identified aurora A kinase as a calgranulin B binding partner, and binding inhibited aurora A kinase activity in a dose-dependent manner. Our findings demonstrate the antitumor effects of calgranulin B in the inflammatory microenvironment and suggest that calgranulin B could be potentially efficacious in the treatment of colon cancer.
Highlights
Despite advances in the diagnosis and treatment of colon cancer, its molecular basis is not completely understood
Calgranulin B protein levels correlated with the presence of stromal inflammatory cells surrounding tumor cells, and calgranulin B promoter methylation was observed in both paired human tissues and colon cancer cell lines
Calgranulin B protein level was analyzed by western blotting in 20 human colon cancer cell lines, two gastric cancer cell lines, one breast cancer cell line, two ovarian cancer cell lines and one cervical cancer cell line
Summary
Despite advances in the diagnosis and treatment of colon cancer, its molecular basis is not completely understood. Increased calgranulin B expression has been reported in malignant tissues from patients with colon cancer [8, 9], ovarian carcinoma [10], prostate cancer [11], invasive ductal carcinomas of the breast [12, 13] and lung adenocarcinoma [14, 15], as well as squamous cell carcinoma of the tongue [16]. Many reports have observed calprotectin-mediated apoptosis and cytotoxicity in human leukemia and colon cancer cell lines, as well as in normal cell types including myeloid cells, mitogen-activated lymphocytes, and fibroblasts [25,26,27,28,29]. Calgranulin B is vital to these calprotectin functions; the role of calgranulin B as a component of the calprotectin heterodimer have been well researched, but few studies have explored the role of calgranulin B alone
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