An Oncogenic Hub pCatenin as a Molecular Target for Cancer Therapeutics


1 Introduction 262

2 The Wnt/ß-Catenin Signaling Pathway 262

3 Regulation of Nuclear ß-Catenin Activity 264

3.1 Structural Features of ß-Catenin 264

3.2 Target Gene Activation by ß-Catenin 265

3.3 Co-Activators for ß-Catenin 266

3.4 ß-Catenin Antagonists 268

4 Wnt/ß-Catenin Signaling in Cancer 269

5 Therapeutic Interventions Targeting ß-Catenin Signaling Activity 271

5.1 Existing Drugs That Suppress ß-Catenin Activity 272

5.2 Small-Molecule Inhibitors 272

5.3 Other Potential Therapeutic Targets in ß-Catenin Signaling 274

6 Conclusions and Perspective 275

References 276

Abstract The Wnt/p-catenin signaling pathway plays diverse roles in embryonic development and in maintenance of organs and tissues in adults. Activation of this signaling cascade inhibits degradation of the pivotal component P-catenin, which in turn stimulates transcription of downstream target genes. Over the past two decades, intensive worldwide investigations have yielded considerable progress toward understanding the cellular and molecular mechanisms of Wnt signaling and its involvement in the pathogenesis of a range of human diseases. Remarkably, P-catenin signaling is aberrantly activated in greater than 70% of colorectal cancers and to a lesser extent in other tumor types, promoting cancer cell proliferation, survival and migration. Accordingly, P-catenin has gained recognition as an enticing molecular target for cancer therapeutics. Disruption of protein-protein interactions essential for P-catenin activity holds immense promise for the development of novel anti-cancer drugs. In this review, we focus on the regulation of P-catenin-dependent transcriptional activation and discuss potential therapeutic opportunities to block this signaling pathway in cancer.

K.-I. Takemaru

Department of Pharmacological Sciences, State University of New York at Stony Brook,

Stony Brook, NY 11794, USA

[email protected]

E. Klussmann, J. Scott (eds.) Protein-Protein Interactions as New Drug Targets. 261

Handbook of Experimental Pharmacology 186, © Springer-Verlag Berlin Heidelberg 2008

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