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J. Cell Biol. 157 (3): 429-440

Copyright © 2002 by the Rockefeller University Press.

Article

Wnt signaling promotes oncogenic transformation by inhibiting c-Myc–induced apoptosis

Zongbing You1, Daniel Saims1, Shaoqiong Chen1, Zhaocheng Zhang1, Denis C. Guttridge5, Kun-liang Guan2,3, Ormond A. MacDougald2,4, Anthony M.C. Brown6, Gerard Evan7, Jan Kitajewski8, and Cun-Yu Wang1,2

1 Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, School of Dentistry
2 Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109
3 Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109
4 Department of Physiology, University of Michigan, Ann Arbor, MI 48109
5 Division of Human Genetics, Department of Medical Microbiology and Immunology, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
6 Strang Cancer Research Laboratory, The Rockefeller University, and Department of Cell Biology and Anatomy, Weill Medical College of Cornell University, New York, NY 10021
7 Comprehensive Cancer Center, University of California-San Francisco, San Francisco, CA 94143
8 Department of Pathology and Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY 10021

Address correspondence to Cun-Yu Wang, Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109-1078. Tel.: 734-615-4386. Fax: 734-764-2425. E-mail: cunywang{at}umich.edu

Abstract: Aberrant activation of the Wnt/ß-catenin signaling pathway is associated with numerous human cancers and often correlates with the overexpression or amplification of the c-myc oncogene. Paradoxical to the cellular transformation potential of c-Myc is its ability to also induce apoptosis. Using an inducible c-MycER expression system, we found that Wnt/ß-catenin signaling suppressed apoptosis by inhibiting c-Myc–induced release of cytochrome c and caspase activation. Both cyclooxygenase 2 and WISP-1 were identified as effectors of the Wnt-mediated antiapoptotic signal. Soft agar assays showed that neither c-Myc nor Wnt-1 alone was sufficient to induce cellular transformation, but that Wnt and c-Myc coordinated in inducing transformation. Furthermore, coexpression of Wnt-1 and c-Myc induced high-frequency and rapid tumor growth in nude mice. Extensive apoptotic bodies were characteristic of c-Myc–induced tumors, but not tumors induced by coactivation of c-Myc and Wnt-1, indicating that the antiapoptotic function of Wnt-1 plays a critical role in the synergetic action between c-Myc and Wnt-1. These results elucidate the molecular mechanisms by which Wnt/ß-catenin inhibits apoptosis and provide new insight into Wnt signaling-mediated oncogenesis.

Key Words: apoptosis; ß-catenin; c-Myc; oncogenesis; Wnt signaling

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