Mandili, Giorgia and Khadjavi, Amina and Gallo, Valentina and Minero, Valerio Giacomo and Bessone, Luca and Carta, Francesco and Giribaldi, Giuliana and Turrini, Francesco Michelangelo (2012) Characterization of the protein ubiquitination response induced by Doxorubicin. FEBS Journal, Vol. 279 (12), p. 2182-2191. eISSN 1742-4658. Article.
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Doxorubicin is commonly considered to exert its anti-tumor activity by triggering the apoptosis of cancer cells through DNA damage. Recent reports have shown that Doxorubicin elicits a marked HSP response and that either inhibition or silencing of HSPs enhance the Doxorubicin apoptotic effect in neuroblastoma (NB) 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 NB cells caused: i) dose-dependent over-ubiquitination of a specific set of proteins in absence of measurable inhibition of proteasome, ii) protein ubiquination patterns similar to Bortezomib, a proteasome inhibitor, iii) depletion and loss of activity of ubiquitinated enzymes such as lactate dehydrogenase and α-enolase; iv) decrease of HSP27 solubility, likely a consequence of its binding to denatured proteins. Comprehensively, these data strongly reinforce the hypothesis that Doxorubicin might also exert its effect by action on protein status.
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