ErbB protein modifications are secondary to severe cell membrane alterations induced by elisidepsin treatment

Tímea Váradi, Janos Roszik, Duarte Lisboa, G. Vereb, José Manuel Molina-Guijarro, Carlos M. Galmarini, J. Szöllősi, Peter Nagy

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)91-99
Number of pages9
JournalEuropean Journal of Pharmacology
Volume667
Issue number1-3
DOIs
Publication statusPublished - Sep 30 2011

Fingerprint

Cell Membrane
Proteins
elisidepsin
Fluorescence Polarization
Membranes
CHO Cells
Fluorescent Dyes
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Transfection
Anti-Idiotypic Antibodies
Necrosis
Lipids
Cell Line
Antibodies
Neoplasms

Keywords

  • Elisidepsin
  • ErbB proteins
  • FRET
  • Liquid ordered domain

ASJC Scopus subject areas

  • Pharmacology

Cite this

ErbB protein modifications are secondary to severe cell membrane alterations induced by elisidepsin treatment. / Váradi, Tímea; Roszik, Janos; Lisboa, Duarte; Vereb, G.; Molina-Guijarro, José Manuel; Galmarini, Carlos M.; Szöllősi, J.; Nagy, Peter.

In: European Journal of Pharmacology, Vol. 667, No. 1-3, 30.09.2011, p. 91-99.

Research output: Contribution to journalArticle

Váradi, Tímea ; Roszik, Janos ; Lisboa, Duarte ; Vereb, G. ; Molina-Guijarro, José Manuel ; Galmarini, Carlos M. ; Szöllősi, J. ; Nagy, Peter. / ErbB protein modifications are secondary to severe cell membrane alterations induced by elisidepsin treatment. In: European Journal of Pharmacology. 2011 ; Vol. 667, No. 1-3. pp. 91-99.
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