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First published on January 11, 2006; DOI: 10.1124/mol.105.018572

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Received for publication September 6, 2005.
Revised January 6, 2006.
Accepted for publication January 6, 2006.

2-Cyano-3,12-dioxooleana-1,9(11)-diene-28-oic acid (CDDO) Disrupts Microtubule Polymerization: A Possible Mechanism Contributing to Apoptosis

Robin D Couch 1, Neil J Ganem 2, Ming Zhou 3, Veljko M Popov 1, Tadashi Honda 1, Timothy D Veenstra 3, Michael B Sporn 2, Amy C Anderson 1*

1 Dartmouth College 2 Dartmouth Medical School 3 NCI-Frederick

* Address correspondence to: E-mail: amy.c.anderson{at}dartmouth.edu

Abstract

The semi-synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) has several biological activities, including the induction of apoptosis in many cancer cell lines. To identify potential protein targets, immobilized biotinylated-CDDO was used to screen the proteome of a human lymphoma cell line (U937) sensitive to CDDO-induced apoptosis. Tubulin was identified as one of several putative targets of CDDO. CDDO was shown to selectively bind to tubulin, with a dissociation constant of ~7 µM, and to disrupt microtubules both in vivo and in vitro. CDDO inhibits tubulin polymerization in vitro, possibly through interactions with a hydrophobic site on {beta}-tubulin. The CDDO-tubulin interaction may also involve a reversible 1,4-addition with a protein sulfhydryl group. Unlike other known spindle poisons, CDDO does not result in a temporal increase in the mitotic index. Rather, CDDO appears to initiate apoptosis early in M phase.


Key words: Mass Spectroscopy, Receptor binding studies, Apoptosis, Protein targets, Mechanisms of cell killing/apoptosis


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