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Mitogenic signalling by B2 bradykinin receptor in epithelial breast cells.
J Cell Physiol. 2004 Oct; 201(1):84-96.JC

Abstract

The kinin peptides are released during inflammation and are amongst the most potent known mediators of vasodilatation, pain, and oedema. A role in the modulation or induction of healthy breast tissue growth has been postulated for tissue kallikrein present in human milk. Moreover, tissue kallikrein was found in malignant human breast tissue and bradykinin (BK) stimulates the proliferation of immortalised breast cancer cells. Aim of the present article was to investigate whether BK also exerts mitogenic activity in normal breast epithelial cells and partially characterise the signalling machinery involved. Results show that BK increased up to 2-fold the 24 h proliferation of breast epithelial cells in primary culture, and that the BK B2 receptor (not B1) inhibitor alone fully blocked the BK response. Intracellular effects of B2 stimulation were the following: (a) the increase of free intracellular Ca(2+) concentration by a mechanism dependent upon the phospholipase C (PLC) activity; (b) the cytosol-to-membrane translocation of conventional (PKC)-alpha and -beta isozymes, novel PKC-delta, -epsilon, and -eta isozymes; (c) the phosphorylation of the extracellular-regulated kinase 1 and 2 (ERK1/2); and (d) the stimulation of the expression of c-Fos protein. EGF, a well known stimulator of cell proliferation, regulated the proliferative response in human epithelial breast cells to the same extent of BK. The effects of BK on proliferation, ERK1/2 phosphorylation, and c-Fos expression were abolished by GF109203X, which inhibits PKC-delta isozyme. Conversely, Gö6976, an inhibitor of PKC-alpha and -beta isozymes, and the 18-h treatment of cells with PMA, that led to the complete down-regulation of PKC-alpha, -beta, -epsilon, and -eta, but not of PKC-delta, did not have any effect, thereby indicating that the PKC-delta mediates the mitogenic signalling of BK. Phosphoinositide 3-kinase (PI3K), tyrosine kinase of the epidermal growth factor receptor (EGFR), and mitogen activated protein kinase kinases (MEK) inhibitors were also tested. The results suggest that EGFR, PI3K, and ERK are required for the proliferative effects of BK. In addition, the BK induced cytosol-to-membrane translocation of PKC-delta was blocked by PI3K inhibition, suggesting that PI3K is upstream to PKC-delta. In conclusion, BK has mitogenic actions in cultured human epithelial breast cells; the activation of PKC-delta through B2 receptor acts in concert with ERK and PI3K pathways to induce cell proliferation.

Authors+Show Affiliations

Laboratory of Cellular Physiology, Department of Biological and Environmental Sciences and Technologies, Ecotekne, Via Prov.le per Monteroni, Lecce, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15281091

Citation

Greco, S, et al. "Mitogenic Signalling By B2 Bradykinin Receptor in Epithelial Breast Cells." Journal of Cellular Physiology, vol. 201, no. 1, 2004, pp. 84-96.
Greco S, Muscella A, Elia MG, et al. Mitogenic signalling by B2 bradykinin receptor in epithelial breast cells. J Cell Physiol. 2004;201(1):84-96.
Greco, S., Muscella, A., Elia, M. G., Romano, S., Storelli, C., & Marsigliante, S. (2004). Mitogenic signalling by B2 bradykinin receptor in epithelial breast cells. Journal of Cellular Physiology, 201(1), 84-96.
Greco S, et al. Mitogenic Signalling By B2 Bradykinin Receptor in Epithelial Breast Cells. J Cell Physiol. 2004;201(1):84-96. PubMed PMID: 15281091.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitogenic signalling by B2 bradykinin receptor in epithelial breast cells. AU - Greco,S, AU - Muscella,A, AU - Elia,M G, AU - Romano,S, AU - Storelli,C, AU - Marsigliante,Santo, PY - 2004/7/29/pubmed PY - 2004/10/22/medline PY - 2004/7/29/entrez SP - 84 EP - 96 JF - Journal of cellular physiology JO - J. Cell. Physiol. VL - 201 IS - 1 N2 - The kinin peptides are released during inflammation and are amongst the most potent known mediators of vasodilatation, pain, and oedema. A role in the modulation or induction of healthy breast tissue growth has been postulated for tissue kallikrein present in human milk. Moreover, tissue kallikrein was found in malignant human breast tissue and bradykinin (BK) stimulates the proliferation of immortalised breast cancer cells. Aim of the present article was to investigate whether BK also exerts mitogenic activity in normal breast epithelial cells and partially characterise the signalling machinery involved. Results show that BK increased up to 2-fold the 24 h proliferation of breast epithelial cells in primary culture, and that the BK B2 receptor (not B1) inhibitor alone fully blocked the BK response. Intracellular effects of B2 stimulation were the following: (a) the increase of free intracellular Ca(2+) concentration by a mechanism dependent upon the phospholipase C (PLC) activity; (b) the cytosol-to-membrane translocation of conventional (PKC)-alpha and -beta isozymes, novel PKC-delta, -epsilon, and -eta isozymes; (c) the phosphorylation of the extracellular-regulated kinase 1 and 2 (ERK1/2); and (d) the stimulation of the expression of c-Fos protein. EGF, a well known stimulator of cell proliferation, regulated the proliferative response in human epithelial breast cells to the same extent of BK. The effects of BK on proliferation, ERK1/2 phosphorylation, and c-Fos expression were abolished by GF109203X, which inhibits PKC-delta isozyme. Conversely, Gö6976, an inhibitor of PKC-alpha and -beta isozymes, and the 18-h treatment of cells with PMA, that led to the complete down-regulation of PKC-alpha, -beta, -epsilon, and -eta, but not of PKC-delta, did not have any effect, thereby indicating that the PKC-delta mediates the mitogenic signalling of BK. Phosphoinositide 3-kinase (PI3K), tyrosine kinase of the epidermal growth factor receptor (EGFR), and mitogen activated protein kinase kinases (MEK) inhibitors were also tested. The results suggest that EGFR, PI3K, and ERK are required for the proliferative effects of BK. In addition, the BK induced cytosol-to-membrane translocation of PKC-delta was blocked by PI3K inhibition, suggesting that PI3K is upstream to PKC-delta. In conclusion, BK has mitogenic actions in cultured human epithelial breast cells; the activation of PKC-delta through B2 receptor acts in concert with ERK and PI3K pathways to induce cell proliferation. SN - 0021-9541 UR - https://www.unboundmedicine.com/medline/citation/15281091/Mitogenic_signalling_by_B2_bradykinin_receptor_in_epithelial_breast_cells_ L2 - https://doi.org/10.1002/jcp.20052 DB - PRIME DP - Unbound Medicine ER -