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

J. Cell Biol., 29 April 2002
Vol. 157, Issue 3, p. 429-440
DOI: 10.1083/jcb.200201110

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

  1. Zongbing You1,
  2. Daniel Saims1,
  3. Shaoqiong Chen1,
  4. Zhaocheng Zhang1,
  5. Denis C. Guttridge5,
  6. Kun-liang Guan2,3,
  7. Ormond A. MacDougald2,4,
  8. Anthony M.C. Brown6,
  9. Gerard Evan7,
  10. Jan Kitajewski8, and
  11. Cun-Yu Wang1,2
  1. 1Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, School of Dentistry
  2. 2Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109
  3. 3Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109
  4. 4Department of Physiology, University of Michigan, Ann Arbor, MI 48109
  5. 5Division of Human Genetics, Department of Medical Microbiology and Immunology, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
  6. 6Strang Cancer Research Laboratory, The Rockefeller University, and Department of Cell Biology and Anatomy, Weill Medical College of Cornell University, New York, NY 10021
  7. 7Comprehensive Cancer Center, University of California-San Francisco, San Francisco, CA 94143
  8. 8Department of Pathology and Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY 10021
  1. 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/β-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/β-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/β-catenin inhibits apoptosis and provide new insight into Wnt signaling-mediated oncogenesis.

  • apoptosis; β-catenin; c-Myc; oncogenesis; Wnt signaling
  • Submitted: 25 January 2002
  • Revision received 15 March 2002
  • Accepted: 19 March 2002

Citation:

Z. You, D. Saims, S. Chen, Z. Zhang, D. C. Guttridge, K.-l. Guan, O. A. MacDougald, A. M. Brown, G. Evan, J. Kitajewski, and C.-Y. Wang, Wnt signaling promotes oncogenic transformation by inhibiting c-Myc–induced apoptosis. J. Cell Biol. 157, 429-440 (2002).

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Y. Ding, S. Su, W. Tang, X. Zhang, S. Chen, G. Zhu, J. Liang, W. Wei, Y. Guo, L. Liu et al.
J. Cell Sci. 127, 4833-4845 (15 November 2014)

RNA-binding protein HuR promotes growth of small intestinal mucosa by activating the Wnt signaling pathway
L. Liu, E. Christodoulou-Vafeiadou, J. N. Rao, T. Zou, L. Xiao, H. Kyoung Chung, H. Yang, M. Gorospe, D. Kontoyiannis, J.-Y. Wang et al.
Mol. Biol. Cell 25, 3308-3318 (1 November 2014)

Wnt5a-Induced Wnt1-Inducible Secreted Protein-1 Suppresses Vascular Smooth Muscle Cell Apoptosis Induced by Oxidative Stress
C. Mill, B. A. Monk, H. Williams, S. J. Simmonds, J. Y. Jeremy, J. L. Johnson, and S. J. George
Arterioscler. Thromb. Vasc. Bio. 34, 2449-2456 (1 November 2014)

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
Carcinogenesis 35, 1284-1291 (1 June 2014)

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
Anticancer Res 33, 2435-2440 (1 June 2013)

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
Anticancer Res 32, 4697-4707 (1 November 2012)

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.
Cancer Res. 72, 2589-2599 (15 May 2012)

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
Am. J. Physiol. Cell Physiol. 302, C277-C285 (1 January 2012)

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
In Vivo 25, 887-893 (1 November 2011)

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
Sci Signal 4, ra65-ra65 (4 October 2011)

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
In Vivo 25, 325-333 (1 May 2011)

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
Anticancer Res 31, 725-730 (1 February 2011)

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
In Vivo 25, 99-103 (1 January 2011)

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
Molecular Cancer Therapeutics 7, 1633-1638 (1 June 2008)

Wnt/{beta}-catenin Inhibits Dental Pulp Stem Cell Differentiation
E.L. Scheller, J. Chang, and C.Y. Wang
JDR 87, 126-130 (1 February 2008)

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
J Biol Chem 282, 30938-30948 (19 October 2007)

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.
Cancer Res. 67, 901-910 (1 February 2007)

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
Cancer Res. 66, 175-183 (1 January 2006)

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
JCO 23, 8765-8773 (1 December 2005)

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, R. Buttyan et al.
Cancer Res. 65, 5263-5271 (15 June 2005)

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, D. M. Jablons et al.
Cancer Res. 65, 743-748 (1 February 2005)

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
J Biol Chem 279, 50670-50675 (3 December 2004)

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
J Biol Chem 279, 35503-35509 (20 August 2004)

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
Cancer Res. 64, 3474-3478 (15 May 2004)

EGF receptor signalling protects smooth-cuticle cells from apoptosis during Drosophila ventral epidermis development
S. Urban, G. Brown, and M. Freeman
Development 131, 1835-1845 (15 April 2004)

Phosphorylation by Glycogen Synthase Kinase-3 Controls c-Myc Proteolysis and Subnuclear Localization
M. A. Gregory, Y. Qi, and S. R. Hann
J Biol Chem 278, 51606-51612 (19 December 2003)

Potential Role of Microsomal Prostaglandin E Synthase-1 in Tumorigenesis
D. Kamei, M. Murakami, Y. Nakatani, Y. Ishikawa, T. Ishii, and I. Kudo
J Biol Chem 278, 19396-19405 (23 May 2003)

{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
Clin. Cancer Res. 9, 1801-1807 (1 May 2003)

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
J. Cell Sci. 116, 1137-1149 (15 March 2003)

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Q. Zeng, L. K. McCauley, and C.-Y. Wang
J Biol Chem 277, 50137-50142 (13 December 2002)

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
J Biol Chem 277, 38239-38244 (4 October 2002)

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