TY - JOUR
T1 - ErbB protein modifications are secondary to severe cell membrane alterations induced by elisidepsin treatment
AU - Váradi, Tímea
AU - Roszik, Janos
AU - Lisboa, Duarte
AU - Vereb, György
AU - Molina-Guijarro, José Manuel
AU - Galmarini, Carlos M.
AU - Szöllosi, János
AU - Nagy, Peter
N1 - Funding Information:
This work has been supported by research grants from the Hungarian Scientific Research Fund ( K72677 , K68763 ), from the European Commission ( LSHC-CT-2005-018914 , MCRTN-CT-2006-035946-2 ) and the New Hungary Development Plan co-financed by the European Social Fund and the European Regional Development Fund ( TÁMOP-4.2.2-08/1-2008-0019 , TÁMOP-4.2.1/B-09/1/KONV-2010-0007 ).
PY - 2011/9/30
Y1 - 2011/9/30
N2 - Elisidepsin is a marine-derived anti-tumor agent with unique mechanism of action. It has been suggested to induce necrosis associated with severe membrane damage. Since indirect evidence points to the involvement of ErbB receptor tyrosine kinases and lipid rafts in the mechanism of action of elisidepsin, we investigated the effect of the drug on the distribution of ErbB proteins and systematically compared the elisidepsin sensitivity of cell lines overexpressing ErbB receptors. Stable expression of a single member of the ErbB family (ErbB1-3) or co-transfection of ErbB2 and ErbB3 did not modify the elisidepsin sensitivity of CHO and A431 cells. However, elisidepsin induced the redistribution of ErbB3 and two GPI-anchored proteins (transfected GPI-anchored eGFP and placental alkaline phosphatase) from the plasma membrane to intracellular vesicles without comparable effects on ErbB1 and ErbB2. Elisidepsin increased the binding of a conformational sensitive anti-ErbB3 antibody without modifying the binding of other ErbB2 or ErbB3 antibodies, and it decreased the homoassociation of both ErbB2 and ErbB3. We also found that elisidepsin decreased the fluorescence anisotropy of a membrane specific fluorescent probe and induced a blue shift in the emission spectrum of Laurdan pointing to significant changes in the order of the plasma membrane possibly associated with the formation of liquid ordered domains. Although the distribution of ErbB proteins is preferentially altered by elisidepsin, our data question their role in determining sensitivity to the drug. We assume that induction of liquid ordered domains is the primary action of elisidepsin leading to all the other observed changes.
AB - Elisidepsin is a marine-derived anti-tumor agent with unique mechanism of action. It has been suggested to induce necrosis associated with severe membrane damage. Since indirect evidence points to the involvement of ErbB receptor tyrosine kinases and lipid rafts in the mechanism of action of elisidepsin, we investigated the effect of the drug on the distribution of ErbB proteins and systematically compared the elisidepsin sensitivity of cell lines overexpressing ErbB receptors. Stable expression of a single member of the ErbB family (ErbB1-3) or co-transfection of ErbB2 and ErbB3 did not modify the elisidepsin sensitivity of CHO and A431 cells. However, elisidepsin induced the redistribution of ErbB3 and two GPI-anchored proteins (transfected GPI-anchored eGFP and placental alkaline phosphatase) from the plasma membrane to intracellular vesicles without comparable effects on ErbB1 and ErbB2. Elisidepsin increased the binding of a conformational sensitive anti-ErbB3 antibody without modifying the binding of other ErbB2 or ErbB3 antibodies, and it decreased the homoassociation of both ErbB2 and ErbB3. We also found that elisidepsin decreased the fluorescence anisotropy of a membrane specific fluorescent probe and induced a blue shift in the emission spectrum of Laurdan pointing to significant changes in the order of the plasma membrane possibly associated with the formation of liquid ordered domains. Although the distribution of ErbB proteins is preferentially altered by elisidepsin, our data question their role in determining sensitivity to the drug. We assume that induction of liquid ordered domains is the primary action of elisidepsin leading to all the other observed changes.
KW - Elisidepsin
KW - ErbB proteins
KW - FRET
KW - Liquid ordered domain
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U2 - 10.1016/j.ejphar.2011.05.064
DO - 10.1016/j.ejphar.2011.05.064
M3 - Article
C2 - 21658382
AN - SCOPUS:80052033225
SN - 0014-2999
VL - 667
SP - 91
EP - 99
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -