title: The cyanobacterial cyclic lipopeptides puwainaphycins F/G are inducing necrosis via cell membrane permeabilization and subsequent unusual actin relocalization.
abstract: Puwainaphycins F and G, moderate cytotoxins, which cause necrotic cell death to mammalian cells, were isolated from the soil cyanobacterium Cylindrospermum alatosporum C24/89. Both compounds have been shown to be cyclic decapeptides containing unusual β-amino fatty acid (2-hydroxy-3-amino-4methyl tetradecanoic acid). Described variants differ in the substitution of threonine by glutamine in the fourth position. Their structures differ from the known puwainaphycins in five amino acids positions as well as in the β-amino fatty acid unit. The rapid interaction of these compounds with the plasma membrane of the mammal cell leads to an elevation of the concentration of intracellular Ca(2+), with kinetics comparable to the well-established calcium ionophore ionomycin. Subsequently, the induction of tyrosine phosphorylation was observed to be followed by the unique transformation of the actin cytoskeleton into ring structures around the nuclei. All of these alterations in the cellular morphology and physiology result in necrotic cell death after ca. 10 h. The IC(50) values were determined to be 2.2 μM for both puwainaphycins. The present data demonstrate the interaction of cyanobacterial secondary metabolites with eukaryotic plasma membrane and point out the possible toxic effects of cyanobacterial lipopeptides for humans.
authors.affiliation: Institute of Microbiology, Department of Phototrophic Microorganisms-ALGATECH, Academy of Sciences of the Czech Republic, Opatovický Mlýn, 379 81 Třeboň, Czech Republic. hrouzekp@gmail.com
authors.forename: Pavel
authors.initials: P
authors.lastname: Hrouzek
authors.forename: Marek
authors.initials: M
authors.lastname: Kuzma
authors.forename: Jan
authors.initials: J
authors.lastname: Černý
authors.forename: Petr
authors.initials: P
authors.lastname: Novák
authors.forename: Radovan
authors.initials: R
authors.lastname: Fišer
authors.forename: Petr
authors.initials: P
authors.lastname: Simek
authors.forename: Alena
authors.initials: A
authors.lastname: Lukešová
authors.forename: Jiří
authors.initials: J
authors.lastname: Kopecký
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects*; D000458:Cyanobacteria / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D055666:Lipopeptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D055666:Lipopeptides; C577099:puwainaphycin F; C577100:puwainaphycin G; D002118:Calcium