The phytochemical piceatannol induces the loss of CBL and CBL-associated proteins.
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.
Klimowicz
Alexander C
AC
Southern Alberta Cancer Research Institute, Department of Oncology, The University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta, Canada T2N-4N1.
Bisson
Sabine A
SA
Hans
Karm
K
Long
Elizabeth M
EM
Hansen
Henrik C
HC
Robbins
Stephen M
SM
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*
D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; C041525:3,3',4,5'-tetrahydroxystilbene; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl