The role of kinin receptors in cancer and therapeutic opportunities

Abstract

Kinins are generated within inflammatory tissue microenvironments, where they exert diverse functions, including cell proliferation, leukocyte activation, cell migration, endothelial cell activation and nociception. These pleiotropic functions depend on signaling through two cross talking receptors, the constitutively expressed kinin receptor 2 (B2R) and the inducible kinin receptor 1 (B1R). We have reviewed evidence, which supports the concept that kinin receptors, especially kinin receptor 1, are promising targets for cancer therapy, since (1) many tumor cells express aberrantly high levels of these receptors; (2) some cancers produce kinins and use them as autocrine factors to stimulate their growth; (3) activation of kinin receptors leads to activation of macrophages, dendritic cells and other cells from the tumor microenvironment; (4) kinins have pro-angiogenic properties; (5) kinin receptors have been implicated in cancer migration, invasion and metastasis; and (6) selective antagonists for either B1R or B2R have shown anti-proliferative, anti-inflammatory, anti-angiogenic and anti-migratory properties. The multiple cross talks between kinin receptors and renin-angiotensin system (RAS) as well as its implications for targeting KKS or RAS for the treatment of malignancies are also discussed. It is expected that B1R antagonists would interfere less with housekeeping functions and therefore would be attractive compounds to treat selected types of cancer. Reliable clinical studies are needed to establish the translatability of these data to human settings and the usefulness of kinin receptor antagonists.

Glioblastoma‐mesenchymal stem cell communication modulates expression patterns of kinin receptors: Possible involvement of bradykinin in information flow

“…This pathway (32,33) and/or alternative possibilities, such as induction of reactive oxygen species (ROS)-dependent pathways, were also shown in brain astrocytes (34). Furthermore, trans-activation of epidermal growth factor receptors (25,35,36), known to be often amplified in its expression rates or mutated in GBM cells, may play a role in the protease cascade activation, where MMP9 is pivotal in modifying extracellular matrix proteins (32,37). Taken together, we hypothesize that kinin receptor expression induction upon direct co-culture with MSC induced calcium influx, possibly promoting MMP9 production in tumor cells.…”

“…These effects were most likely mediated by activation of phosphatidylinositol 3 kinase (PI3) Akt and extracellular signal-regulated kinases (ERK) pathways (29). Kinin receptormodulated proliferation was also observed for microglial cells (30) as well as for bladder carcinoma (14) and other cancers (25).…”

“…Although kinin receptors in brain tumors have been studied mostly with respect to their physiological functions to possibly raise blood-tumor-barrier permeability (23) and affect angiogenesis (24,25), here we focused on their impact on glioblastoma (GBM) cell invasion. In vivo studies on kinin B1 (B1R) and B2 receptors (B2R) revealed that B2R was increasingly expressed with augmenting malignancy of glioma (16) and GBM cells (26).…”

In Vivo Radioimaging of Bradykinin Receptor B1, a Widely Overexpressed Molecule in Human Cancer

“…These G-protein-coupled receptors bind bradykinin and kallidin, which are produced by enzymatic cleavage of kininogens (1). The overexpression of the B1 and B2 receptors (B1R and B2R) has been documented in many cancers (2). While B2R is ubiquitously expressed, B1R has low endogenous expression in normal tissues.…”

Plasma Kallikrein-Kinin system mediates immune-mediated renal injury in trichloroethylene-sensitized mice

“…It is now understood that the overall effect of the KKS can be influenced by kinin receptor level (da Costa et al 2014) and BK exerts its effects via activation of two Gprotein-coupled kinin receptors, B1R and B2R. B1R is virtually absent in healthy state but up-regulated during tissue damage or inflammation.…”