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Characterization of the protein ubiquitination response induced by Doxorubicin
Author(s) -
Mandili Giorgia,
Khadjavi Amina,
Gallo Valentina,
Minero Valerio G.,
Bessone Luca,
Carta Franco,
Giribaldi Giuliana,
Turrini Francesco
Publication year - 2012
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2012.08602.x
Subject(s) - doxorubicin , heat shock protein , proteasome , hsp27 , ubiquitin , proteasome inhibitor , dna damage , apoptosis , chemistry , cancer research , biology , microbiology and biotechnology , hsp70 , biochemistry , dna , chemotherapy , genetics , gene
Doxorubicin is commonly considered to exert its anti‐tumor activity by triggering apoptosis of cancer cells through DNA damage. Recent reports have shown that Doxorubicin elicits a marked heat shock response, and that either inhibition or silencing of heat shock proteins enhance the Doxorubicin apoptotic effect in neuroblastoma cells. In order to investigate whether Doxorubicin may also act through protein modification, we performed a proteomic analysis of ubiquitinated proteins. Here we show that nanomolar Doxorubicin treatment of neuroblastoma cells caused: (a) dose‐dependent over‐ubiquitination of a specific set of proteins in the absence of measurable inhibition of proteasome, (b) protein ubiquination patterns similar to those with Bortezomib, a proteasome inhibitor, (c) depletion and loss of activity of ubiquitinated enzymes such as lactate dehydrogenase and α‐enolase, and (d) a decrease in HSP27 solubility, probably a consequence of its binding to denatured proteins. These data strongly reinforce the hypothesis that Doxorubicin may also exert its effect by damaging proteins.