DISRUPTION OF CELLULAR SIGNALING PATHWAYS BY DAUNOMYCIN THROUGH DESTABILIZATION OF NONLAMELLAR MEMBRANE STRUCTURES

被引:96
作者
ESCRIBA, PV [1 ]
SASTRE, M [1 ]
GARCIASEVILLA, JA [1 ]
机构
[1] UNIV BALEARIC ISL,DEPT FUNDAMENTAL BIOL & HLTH SCI,NEUROPHARMACOL LAB,E-07071 PALMA DE MALLORCA,SPAIN
关键词
GUANINE NUCLEOTIDE-BINDING REGULATORY PROTEIN; PROTEIN KINASE C; ALPHA(2)-ADRENERGIC RECEPTORS; TRANSDUCTION; LIPOSOMES;
D O I
10.1073/pnas.92.16.7595
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Albeit anthracyclines are widely used in the treatment of solid tumors and leukemias, their mechanism of action has not been elucidated. The present study gives relevant information about the role of nonlamellar membrane structures in signaling pathways, which could explain how anthracyclines can exert their cytocidal action without entering the cell [Tritton, T.R. and Yee, G, (1982) Science 217, 248-250]. The anthracycline daunomycin reduced the formation of the nonlamellar hexagonal (H-II) phase (i.e., the hexagonal phase propensity), stabilizing the bilayer structure of the plasma membrane by a direct interaction with membrane phospholipids. As a consequence, various cellular events involved in signal transduction, such as membrane fusion and membrane association of peripheral proteins [e.g., guanine nucleotide-binding regulatory proteins (G proteins and protein kinase C-cup)], where nonlamellar structures (negative intrinsic monolayer curvature strain) are required, were altered by the presence of daunomycin. Functionally, daunomycin also impaired the expression of the high-affinity state of a G protein-coupled receptor (ternary complex for the alpha(2)-adrenergic receptor) due to G-protein dissociation from the plasma membrane. In vivo, daunomycin also decreased the levels of membrane-associated G proteins and protein kinase C-alpha beta in the heart. The occurrence of such nonlamellar structures favors the association of these peripheral proteins with the plasma membrane and prevents daunomycin-induced dissociation. These results reveal an important role of the lipid component of the cell membrane in signal transduction and its alteration by anthracyclines.
引用
收藏
页码:7595 / 7599
页数:5
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