The phytochemical piceatannol induces the loss of CBL and CBL-associated proteins

• Published in: Molecular cancer therapeutics Vol. 8; no. 3; pp. 602 - 614
• Main Authors: Klimowicz, Alexander C, Bisson, Sabine A, Hans, Karm, Long, Elizabeth M, Hansen, Henrik C, Robbins, Stephen M
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.03.2009
• Subjects: 3T3 Cells; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Cbl; Cells, Cultured; Humans; K562 Cells; Mice; Models, Biological; Neoplasms - metabolism; Neoplasms - pathology; O-benzoquinone; Oxidation-Reduction - drug effects; piceatannol; Protein Binding - drug effects; Protein Processing, Post-Translational - drug effects; protein-loss; Proto-Oncogene Proteins c-cbl - metabolism; reactive oxygen species; Signal Transduction - drug effects; stilbene; Stilbenes - pharmacology
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-0891

Piceatannol is a naturally occurring bioactive stilbene with documented antileukemic properties. It has been extensively used as a Syk-selective protein tyrosine kinase inhibitor for the study of various signaling pathways. Herein, we show that the hydroxystilbene, piceatannol, and related catechol ring-containing compounds are able to induce the loss of the Cbl family of proteins. Normal cellular Cbl-regulatory mechanisms were not involved in this process. Screening of a small library of piceatannol-like compounds indicated that aromaticity and a catechol ring were required for the induction of Cbl loss. Further examination of these two chemical properties showed that the oxidative conversion of the catechol ring of piceatannol into a highly reactive O -benzoquinone was the cause of piceatannol-induced Cbl loss. Characterization of the Cbl selectivity of piceatannol-induced protein loss revealed that this compound was also able to induce the functional loss of specific Cbl-associated proteins involved in signaling pathways commonly associated with cancer. This work uncovers a new, piceatannol-dependent effect and shows a novel way in which this phenomenon can be exploited to inhibit disease-associated signaling pathways. [Mol Cancer Ther 2009;8(3):602–14]