Studies of the antitumor mechanism of action of dermaseptin B2, a multifunctional cationic antimicrobial peptide, reveal a partial implication of cell surface glycosaminoglycans

Dermaseptin-B2 (DRS-B2) is a multifunctional cationic antimicrobial peptide (CAP) isolated from frog skin secretion. We previously reported that DRS-B2 possesses anticancer and antiangiogenic activities in vitro and in vivo. In the present study, we evaluated the antiproliferative activity of DRS-B2...

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Published in:	PloS one Vol. 12; no. 8; p. e0182926
Main Authors:	Dos Santos, Célia, Hamadat, Sabah, Le Saux, Karen, Newton, Clara, Mazouni, Meriem, Zargarian, Loussiné, Miro-Padovani, Mickael, Zadigue, Patricia, Delbé, Jean, Hamma-Kourbali, Yamina, Amiche, Mohamed
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 10-08-2017 Public Library of Science (PLoS)
Subjects:	Amino Acid Sequence Amino acids Amphibian Proteins - chemistry Amphibian Proteins - pharmacology Analysis Animals Antiangiogenics Anticancer properties Antiinfectives and antibacterials Antimicrobial Cationic Peptides - chemistry Antimicrobial Cationic Peptides - pharmacology Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antitumor activity Anura Bacteria Biology and Life Sciences Biomedical research Biotechnology Cancer Cancer therapies Care and treatment Cations Cell Line, Tumor Cell membranes Cell Proliferation - drug effects Cell surface Chemistry Chlorate Chondroitin sulfate Circular dichroism Circularity Confocal microscopy Cytoplasm Cytoplasmic membranes D-Amino acids Dichroism Drug resistance Flow cytometry Glycosaminoglycans Glycosaminoglycans - metabolism Health aspects Heparan sulfate Humans In vitro methods and tests In vivo methods and tests Internalization Medicine Medicine and Health Sciences Membrane vesicles Membranes Microscopy Mucopolysaccharides Neoplasms - drug therapy Neoplasms - metabolism Neural networks Nuclei Nuclei (cytology) Peptides Physical Sciences Pools Pretreatment Prostate Research and Analysis Methods Secretion Skin Sodium Sodium chlorate Structural analysis Structure-Activity Relationship Sulfates Tumor cell lines Tumor cells Viability France
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Summary:	Dermaseptin-B2 (DRS-B2) is a multifunctional cationic antimicrobial peptide (CAP) isolated from frog skin secretion. We previously reported that DRS-B2 possesses anticancer and antiangiogenic activities in vitro and in vivo. In the present study, we evaluated the antiproliferative activity of DRS-B2 on numerous tumor cell lines, its cell internalization and studies of its molecular partners as well as their influences on its structure. Confocal microscopy using ([Alexa594]-(Cys0)-DRS-B2) shows that in sensitive human tumor cells (PC3), DRS-B2 seems to accumulate rapidly at the cytoplasmic membranes and enters the cytoplasm and the nucleus, while in less sensitive tumor cells (U87MG), DRS-B2 is found packed in vesicles at the cell membrane. Furthermore FACS analysis shows that PC3 cells viability decreases after DRS-B2 treatment while U87 MG seems to be unaffected. However, "pull down" experiments performed with total protein pools from PC3 or U87MG cells and the comparison between the antiproliferative effect of DRS-B2 and its synthetic analog containing all D-amino acids suggest the absence of a stereo-selective protein receptor. Pretreatment of PC3 cells with sodium chlorate, decreases the antiproliferative activity of DRS-B2. This activity is partially restored after addition of exogenous chondroitin sulfate C (CS-C). Moreover, we demonstrate that at nanomolar concentrations CS-C potentiates the antiproliferative effect of DRS-B2. These results highlight the partial implication of glycosaminoglycans in the mechanism of antiproliferative action of DRS-B2. Structural analysis of DRS-B2 by circular dichroism in the presence of increasing concentration of CS-C shows that DRS-B2 adopts an α-helical structure. Finally, structure-activity-relationship studies suggest a key role of the W residue in position 3 of the DRS-B2 sequence for its antiproliferative activity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Current address: Hemostasis and Thrombosis Department (Chemistry Division) Hematology Research Institute Mariano R. Castex National Academy of Medicine, Buenos Aires, Argentina
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0182926