Kinin-generating cellular model obtained from human glioblastoma cell line U-373.

Abstract

Kinins, a group of important pro-inflammatory peptides, are abundantly found in tissues and biological fluids of cancer patients. Bradykinin, the major representative of kinins, induces vascular permeability and, in consequence, promotes tumor expansion. Additionally, the kinin-induced inflammatory responses, especially those mediated by kinin metabolites without the C-terminal arginine residue, lead to enhanced tumor growth. The present study aimed at analyzing the ability of the human glioblastoma cell line U-373, derived from a malignant tumor, to produce kinin peptides. The proteins involved in kinin generation, i.e., the kininogens and the kallikreins, were shown to be expressed in these cells. Moreover, tumor necrosis factor α, a proinflammatory cytokine that mediates tumorigenesis, was found to enhance the expression of enzymes associated with kinin production. The strong binding of kininogen to the cell surface and the enzymatic degradation of this protein by cells suggest the activation of kinin-generating systems. Indeed, glioblastoma cells, pre-treated with tumor necrosis factor α, released kinin peptides from exogenous kininogen. The expression of kinin receptors in these cells was also shown to increase under the influence of this cytokine. Our results suggest that the human glioblastoma cell line U-373 constitutes a good cellular model that can be helpful in cancer research focused on kinininduced inflammation. Furthermore, our findings can contribute to new approaches in cancer treatment with the use of kinin receptor antagonists and inhibitors of kinin production.

Could a plant derived protein potentiate the anticancer effects of a stem cell in brain cancer?

“…A significant down-regulation of the expression of urokinase receptor PlauR, needed for urokinase activity, may have affected other transmembrane proteins via fluidic transmembrane diffusion. We have recently [ 21 ] elucidated that U87 cells via direct crosstalk affect invasion of MSC, which is possibly activated by the kallikrein-kinin system and mediated via bradykinin receptors (BRs) [ 42 , 43 , 45 ]. Therefore, we measured the BR2 expression in U87 cells, MSC and in the coculture.…”

Targeting intracellular B2 receptors using novel cell-penetrating antagonists to arrest growth and induce apoptosis in human triple-negative breast cancer

“…We indeed detected the presence of endogenous kininogens-, kallikreins- and BK-like immunoreactivities in MDA-MB-231 cells not only in the cytoplasmic region, but also in the intranuclear region of MDA-MB-231 cells ( Supplementary Figure 3 ), which were generally characterized by a fine granular speckled cytoplasmic and nuclear staining. Such kinin-generating system was also reported to be present in the human glioblastoma cell line U-373 [ 69 ]. Overall, these results give credence to the possibility that the tumor-derived BK may be active both intracellularly (at nuclear sites) and extracellularly (upon its release) on cancer and stromal cells, thereby contributing to tumor growth and progression.…”

Kinin Peptides Enhance Inflammatory and Oxidative Responses Promoting Apoptosis in a Parkinson’s Disease Cellular Model

“…Nevertheless, the expression of B2R is less vulnerable to changes; this receptor after agonist binding and internalization may recycle to the cell surface [ 13 ]. In addition, BK can be converted to des-Arg metabolites by carboxypeptidases, present in different tissues, including the brain [ 6 , 41 ]. Moreover, BK was also able to induce B1R expression on cell membranes [ 42 ].…”