Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Genetic variants of the Wnt signaling pathway as predictors of recurrence and survival in early-stage non-small cell lung cancer patients.
A. Coscio, D. W. Chang, J. A. Roth, Y. Ye, J. Gu, P. Yang, and X. Wu (2014)
Carcinogenesis
   Abstract »    Full Text »    PDF »
Targeting Renal Cancer with a Combination of WNT Inhibitors and a Bi-Functional Peptide.
C. M. KOLLER, Y. KIM, and I. G. H. SCHMIDT-WOLF (2013)
Anticancer Res 33, 2435-2440
   Abstract »    Full Text »    PDF »
Antagonistic Effect of Small-molecule Inhibitors of Wnt/{beta}-catenin in Multiple Myeloma.
B. A. NARAYANAN, N. A. DOUDICAN, J. PARK, D. XU, N. K. NARAYANAN, R. DASGUPTA, and A. MAZUMDER (2012)
Anticancer Res 32, 4697-4707
   Abstract »    Full Text »    PDF »
Interleukin-17 Promotes Formation and Growth of Prostate Adenocarcinoma in Mouse Models.
Q. Zhang, S. Liu, D. Ge, Q. Zhang, Y. Xue, Z. Xiong, A. B. Abdel-Mageed, L. Myers, S. M. Hill, B. G. Rowan, et al. (2012)
Cancer Res. 72, 2589-2599
   Abstract »    Full Text »    PDF »
Activation of Wnt3a signaling stimulates intestinal epithelial repair by promoting c-Myc-regulated gene expression.
L. Liu, J. N. Rao, T. Zou, L. Xiao, A. Smith, R. Zhuang, D. J. Turner, and J.-Y. Wang (2012)
Am J Physiol Cell Physiol 302, C277-C285
   Abstract »    Full Text »    PDF »
Targeting the Wnt/Beta-catenin Pathway with the Antifungal Agent Ciclopirox Olamine in a Murine Myeloma Model.
Y. KIM, M. SCHMIDT, T. ENDO, D. LU, D. CARSON, and I. G. H. SCHMIDT-WOLF (2011)
In Vivo 25, 887-893
   Abstract »    Full Text »    PDF »
Genome-Wide Analysis of a Wnt1-Regulated Transcriptional Network Implicates Neurodegenerative Pathways.
E. M. Wexler, E. Rosen, D. Lu, G. E. Osborn, E. Martin, H. Raybould, and D. H. Geschwind (2011)
Science Signaling 4, ra65
   Abstract »    Full Text »    PDF »
Increased In vivo Efficacy of Lenalidomide and Thalidomide by Addition of Ethacrynic Acid.
M. SCHMIDT, Y. KIM, S.-M. GAST, T. ENDO, D. LU, D. CARSON, and I. G. H. SCHMIDT-WOLF (2011)
In Vivo 25, 325-333
   Abstract »    Full Text »    PDF »
Influencing the Wnt Signaling Pathway in Multiple Myeloma.
Y. KIM, G. REIFENBERGER, D. LU, T. ENDO, D. A. CARSON, S.-M. GAST, K. MESCHENMOSER, M. NOWAK, and I. G. H. SCHMIDT-WOLF (2011)
Anticancer Res 31, 725-730
   Abstract »    Full Text »    PDF »
Increased In Vivo Efficacy of Lenalidomide by Addition of Piroctone Olamine.
Y. KIM, P. ALPMANN, S. BLAUM-FEDER, S. KRAMER, T. ENDO, D. LU, D. CARSON, and I. G. H. SCHMIDT-WOLF (2011)
In Vivo 25, 99-103
   Abstract »    Full Text »    PDF »
Evaluation of a chemical library of small-molecule Dishevelled antagonists that suppress tumor growth by down-regulating T-cell factor-mediated transcription.
L. You, Z. Xu, C. Punchihewa, D. M. Jablons, and N. Fujii (2008)
Mol. Cancer Ther. 7, 1633-1638
   Abstract »    Full Text »    PDF »
Wnt/{beta}-catenin Inhibits Dental Pulp Stem Cell Differentiation.
E.L. Scheller, J. Chang, and C.Y. Wang (2008)
Journal of Dental Research 87, 126-130
   Abstract »    Full Text »    PDF »
Noncanonical Wnt-4 Signaling Enhances Bone Regeneration of Mesenchymal Stem Cells in Craniofacial Defects through Activation of p38 MAPK.
J. Chang, W. Sonoyama, Z. Wang, Q. Jin, C. Zhang, P. H. Krebsbach, W. Giannobile, S. Shi, and C.-Y. Wang (2007)
J. Biol. Chem. 282, 30938-30948
   Abstract »    Full Text »    PDF »
Tbx3 Is a Downstream Target of the Wnt/{beta}-Catenin Pathway and a Critical Mediator of {beta}-Catenin Survival Functions in Liver Cancer.
C.-A. Renard, C. Labalette, C. Armengol, D. Cougot, Y. Wei, S. Cairo, P. Pineau, C. Neuveut, A. de Reynies, A. Dejean, et al. (2007)
Cancer Res. 67, 901-910
   Abstract »    Full Text »    PDF »
Interleukin-17 Receptor-Like Gene Is a Novel Antiapoptotic Gene Highly Expressed in Androgen-Independent Prostate Cancer.
Z. You, X.-B. Shi, G. DuRaine, D. Haudenschild, C. G. Tepper, S. Hao Lo, R. Gandour-Edwards, R. W. de Vere White, and A. H. Reddi (2006)
Cancer Res. 66, 175-183
   Abstract »    Full Text »    PDF »
Wnt5a Expression Is Associated With the Tumor Proliferation and the Stromal Vascular Endothelial Growth Factor--An Expression in Non-Small-Cell Lung Cancer.
C.-l. Huang, D. Liu, J. Nakano, S. Ishikawa, K. Kontani, H. Yokomise, and M. Ueno (2005)
J. Clin. Oncol. 23, 8765-8773
   Abstract »    Full Text »    PDF »
A Human- and Male-Specific Protocadherin that Acts through the Wnt Signaling Pathway to Induce Neuroendocrine Transdifferentiation of Prostate Cancer Cells.
X. Yang, M.-W. Chen, S. Terry, F. Vacherot, D. K. Chopin, D. L. Bemis, J. Kitajewski, M. C. Benson, Y. Guo, and R. Buttyan (2005)
Cancer Res. 65, 5263-5271
   Abstract »    Full Text »    PDF »
Secreted Frizzled-Related Protein 4 Is Silenced by Hypermethylation and Induces Apoptosis in {beta}-Catenin-Deficient Human Mesothelioma Cells.
B. He, A. Y. Lee, S. Dadfarmay, L. You, Z. Xu, N. Reguart, J. Mazieres, I. Mikami, F. McCormick, and D. M. Jablons (2005)
Cancer Res. 65, 743-748
   Abstract »    Full Text »    PDF »
Global Inhibition of Lef1/Tcf-dependent Wnt Signaling at Its Nuclear End Point Abrogates Development in Transgenic Xenopus Embryos.
T. Deroo, T. Denayer, F. Van Roy, and K. Vleminckx (2004)
J. Biol. Chem. 279, 50670-50675
   Abstract »    Full Text »    PDF »
Wnt10b Inhibits Development of White and Brown Adipose Tissues.
K. A. Longo, W. S. Wright, S. Kang, I. Gerin, S.-H. Chiang, P. C. Lucas, M. R. Opp, and O. A. MacDougald (2004)
J. Biol. Chem. 279, 35503-35509
   Abstract »    Full Text »    PDF »
Inhibition of Wnt-1 Signaling Induces Apoptosis in {beta}-Catenin-Deficient Mesothelioma Cells.
L. You, B. He, K. Uematsu, Z. Xu, J. Mazieres, A. Lee, F. McCormick, and D. M. Jablons (2004)
Cancer Res. 64, 3474-3478
   Abstract »    Full Text »    PDF »
EGF receptor signalling protects smooth-cuticle cells from apoptosis during Drosophila ventral epidermis development.
S. Urban, G. Brown, and M. Freeman (2004)
Development 131, 1835-1845
   Abstract »    Full Text »    PDF »
Phosphorylation by Glycogen Synthase Kinase-3 Controls c-Myc Proteolysis and Subnuclear Localization.
M. A. Gregory, Y. Qi, and S. R. Hann (2003)
J. Biol. Chem. 278, 51606-51612
   Abstract »    Full Text »    PDF »
Potential Role of Microsomal Prostaglandin E Synthase-1 in Tumorigenesis.
D. Kamei, M. Murakami, Y. Nakatani, Y. Ishikawa, T. Ishii, and I. Kudo (2003)
J. Biol. Chem. 278, 19396-19405
   Abstract »    Full Text »    PDF »
{beta}-Catenin-related Anomalies in Apoptosis-resistant and Hormone-refractory Prostate Cancer Cells.
A. de la Taille, M. A. Rubin, M.-W. Chen, F. Vacherot, S. G.-D. de Medina, M. Burchardt, R. Buttyan, and D. Chopin (2003)
Clin. Cancer Res. 9, 1801-1807
   Abstract »    Full Text »    PDF »
A {beta}-catenin survival signal is required for normal lobular development in the mammary gland.
S. B. Tepera, P. D. McCrea, and J. M. Rosen (2003)
J. Cell Sci. 116, 1137-1149
   Abstract »    Full Text »    PDF »
Hepatocyte Growth Factor Inhibits Anoikis by Induction of Activator Protein 1-dependent Cyclooxygenase-2. IMPLICATION IN HEAD AND NECK SQUAMOUS CELL CARCINOMA PROGRESSION.
Q. Zeng, L. K. McCauley, and C.-Y. Wang (2002)
J. Biol. Chem. 277, 50137-50142
   Abstract »    Full Text »    PDF »
Wnt Signaling Protects 3T3-L1 Preadipocytes from Apoptosis through Induction of Insulin-like Growth Factors.
K. A. Longo, J. A. Kennell, M. J. Ochocinska, S. E. Ross, W. S. Wright, and O. A. MacDougald (2002)
J. Biol. Chem. 277, 38239-38244
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882