Human beta-defensins in regulation of biologic patterns of cancer cells

Gerashchenko O.L., Zhuravel E.V., Pogrebnoy P.V., Soldatkina M.

O. Gerashchenko, E. Zhuravel, P. Pogrebnoy, M. Soldatkina

R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology NAS of Ukraine, Kyiv, Ukraine

pogrebnoy@onconet.kiev.ua

Human beta-defensins (hBDs) belong to a family of small cationic peptide antibiotics produced by human epithelial cells and are characterized by wide spectrum of biologic activities. These molecules exert direct antimicrobial action and immunomodulatory activity, and are shown to be involved in many human pathologies including cancer. Beta-defensins are involved also in wound healing processes and may affect proliferation of epithelial cells. To understand the mechanisms of biologic activities of beta-defensins, we have produced two recombinant defensins — hBD-2 and hBD-4 expressed in bacterial cells as GST-hBD-2 or -4 fusion proteins. Analysis of in vitro activity of rec-hBD-2 toward different human cancer cell lines (A341, A549, 3 thyroid cancer cells, 2 melanoma cell lines) has demonstrated that this defensin is capable to affect cell proliferation and viability in a concentration-dependent manner and in nanomolar range may significantly suppress cell growth via cell cycle arrest in G1/S checkpoint, dephosphorylation of pRB and significant suppression of cyclin D1 expression. The action of hBD-2 is not cell type specific, at nanomolar concentrations hBD-2 significantly suppresses colony forming activity of human cancer cells and their migration ability in scratch assay. In vitro hBD-2 may enter tumor cells, could be detected in cell cytoplasm and also in cell nuclei. Similarly, this defensin has been detected in cell nuclei in human lung tumor samples, moreover, in such cases hBD-2 expression levels positively correlated with human lung adenocarcinoma differentiation grade, and negatively correlated with PCNA expression. Hypothetically, concentration-dependent effects of hBD-2 could be explained by its capability to oligomerization. The study of recombinant hBD-4 (presented in details in current issue of Exp Oncol) has demonstrated a concentration-dependent bimodal effect of this defensin on biologic patterns of human cancer cells: in low nanomolar concentrations rec-hBD-4 significantly stimulates cancer cell proliferation and viability, promotes cell cycle progression through G2/M checkpoint, greatly enhances co­lony-forming activity and migration ability of the cells, but at higher concentrations the effects are of opposite character — significant suppression of cell proliferation and viability, cell cycle arrest in G1/S checkpoint, significant inhibition of cell migration and colony forming activity. It’s of interest to analyze further with the use of in vitro system what mechanism is exploited by beta-defensins for cancer cell growth suppression — senescence, MET, other, whether it is reversible or irreversible, and to find applications of this know­ledge in the field of clinical oncology.

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