Abstract
Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to distant organs. Bradykinin (BK) is an inflammatory mediator and has recently been shown to mediate tumor growth and metastasis. The adhesion molecule intercellular adhesion molecule-1 (ICAM-1) plays a critical role during tumor metastasis. The aim of this study was to examine whether BK promotes prostate cancer cell migration via ICAM-1 expression. The motility of cancer cells was increased following BK treatment. Stimulation of prostate cancer cells with BK induced mRNA and protein expression of ICAM-1. Transfection of cells with ICAM-1 small interfering RNA reduced BK-increased cell migration. Pretreatment of prostate cancer cells with B2 receptor, phosphatidylinositol 3-kinase (PI3K), Akt, and activator protein 1 (AP-1) inhibitors or mutants abolished BK-promoted migration and ICAM-1 expression. In addition, treatment with a B2 receptor, PI3K, or Akt inhibitor also reduced BK-mediated AP-1 activation. Our results indicate that BK enhances the migration of prostate cancer cells by increasing ICAM-1 expression through a signal transduction pathway that involves the B2 receptor, PI3K, Akt, and AP-1. Thus, BK represents a promising new target for treating prostate cancer metastasis.
Highlights
Prostate cancer is the most commonly diagnosed malignancy in the USA and other western countries [1]
We hypothesized that intercellular adhesion molecule-1 (ICAM-1) may be involved in the BK-induced migratory ability of human prostate cancer cells
Blocked ICAM-1 expression and BK-mediated cell migration, which was demonstrated in wound-healing and Transwell assays (Figure 1E,F). These results indicate that ICAM-1 up-regulation is involved in BK-promoted cell migration of human prostate cancer cells
Summary
Prostate cancer is the most commonly diagnosed malignancy in the USA and other western countries [1]. Systemic interventions to inhibit the growth and spread of secondary metastasis are necessary for the treatment of advanced patients with disease state [2]. The complex and multi-stage process of formation of secondary tumors at distant sites, called metastasis, is the major cause of mortality in cancer patients [3]. Several steps are involved in the metastasis process, including cellular transformation and tumor growth, angiogenesis, lymphangiogenesis, entry of cancer cells in the circulation by intravasation, invasion of the target organ by extravasation, anchorage and/or attachment to the target organ, and proliferation within the organ parenchyma [4]. The relationship between the migration activity of cancer cells and many of these steps is close and, correlated with tumor metastasis. ICAM-1 may play a critical role in tumorigenesis, and determining the critical role of ICAM-1 disruption may prevent cancer cell metastasis in disease development
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