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Arbeitsgemeinschaft für Medizinisches Bibliothekswesen (AGMB)

ISSN 1865-066X

Science Signaling, Perspective – Cancer: Wnt/β-Catenin and MAPK Signaling: Allies and Enemies in Different Battlefields, April 2012

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GMS Med Bibl Inf 2012;12(1-2):Doc14

doi: 10.3205/mbi000250, urn:nbn:de:0183-mbi0002509

This is the original version of the article.
The translated version can be found at: http://www.egms.de/de/journals/mbi/2012-12/mbi000250.shtml

Published: July 5, 2012

© 2012 Forsythe.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Abstract

Research published in Science Signaling [1] represents major advances in cell signaling in many disciplines, including the rapidly expanding areas of signaling networks, systems biology, synthetic biology, computation and modeling of regulatory pathways, and drug discovery. The published research content offers discoveries that substantially refine current understanding of important signaling processes, provide new concepts, and are likely to find application in multiple biological systems. Two papers this year in Science Signaling describe previously unknown links between two signaling pathways that are associated with cancer – melanoma and colon cancer. The Perspective, “Wnt/β-catenin and MAPK Signaling: Allies and Enemies in Different Battlefields,” describes how both studies have implications for the development of combination therapies for skin and colon cancer [2].

Keywords: cell death, colon cancer, combinatorial strategy, intestinal tumorigenesis, MAPK, melanoma, oncogenic, protein kinases, signaling pathways, skin cancer, tumors, Wnt/beta-catenin


Science Signaling, Perspective – Cancer: Wnt/β-Catenin and MAPK Signaling: Allies and Enemies in Different Battlefields, April 2012

Melanoma is an aggressive form of skin cancer associated with several different environmental and genetic risk factors. Many melanomas harbor mutations that activate signaling through the mitogen-activated protein kinase (MAPK) pathway, including mutations in the kinase BRAF. BRAF inhibitors are used clinically to treat melanoma, and although many patients’ tumors respond to BRAF inhibitors initially, some of these tumors develop resistance to the drug and stop responding. Biechele et al. reported that inhibiting BRAF of the MAPK pathway and activating another pathway, the Wnt/β-catenin pathway, simultaneously increased cell death in some melanoma cells, suggesting that this combinatorial strategy might be useful for designing more effective clinical therapies [3].

Because the Wnt/β-catenin signaling pathway is oncogenic in most cancers, yet anti-oncogenic and a marker for good prognosis in melanoma, Biechele and colleagues searched for previously unknown regulators of Wnt/β-catenin signaling in melanoma. They used an RNA interference-based genetic screen for protein kinases, whose silencing synergized with Wnt in stimulating β-catenin transcriptional activity in a human melanoma cell line. Using this screen, they unexpectedly found that silencing of BRAF enhanced the stabilization of β-catenin in the presence of Wnt. This finding is particularly interesting because oncogenic mutations in BRAF occur in about 60% of human melanomas.

During an interview, Biechele et al. explain that “in particular, melanoma has been refractory to conventional chemotherapies and radiation therapies, so identifying innovative and novel approaches to this cancer will undoubtedly be necessary for coming up with treatments that are both effective and sustainable over the long term for patients [4]” (Figure 1 [Fig. 1]).

The relationship between the Wnt/β-catenin and MAPK signaling pathways was also investigated by Jeong et al. [5] in the context of intestinal tumorigenesis. Compared with the response to simultaneous activation of these two pathways in melanoma, in colon cancer, the opposite response was observed: the Wnt/β-catenin and MAPK signaling synergized in a combined effort to promote transformation. Jeong et al. discovered that the negative regulators of the Wnt/β-catenin signaling, which are the components of the β-catenin destruction complex, conspired to trigger the degradation of β-catenin as well as Ras, which is the protein that activates the first kinase in the MAPK cascade. In the context of intestinal cancer, the result of the aberrant activation of Wnt/β-catenin signaling was the stabilization of both β-catenin and Ras through the inactivation of the destruction complex.

Both studies raised an important point in common: Axin, which is a constituent of the destruction complex, seems to play a decisive role in controlling the interplay between Wnt/β-catenin and MAPK signaling. Axin is the concentration-limiting component in the destruction complex and these two research papers indicate that Axin is a key node for coordination between these two pathways. This “crosstalk” between Wnt/β-catenin and MAPK signaling in melanoma and colon cancer provides insight into the development of customized combination therapies, specific for these two divergent cancers.


References

1.
Science Signaling. Washington, DC: American Association for the Advancement of Science. Available from: http://stke.sciencemag.org External link
2.
Guardavaccaro D, Clevers H. Wnt/β-catenin and MAPK signaling: allies and enemies in different battlefields. Sci Signal. 2012 Apr 10;5(219):pe15. DOI: 10.1126/scisignal.2002921 External link
3.
Biechele TL, Kulikauskas RM, Toroni RA, Lucero OM, Swift RD, James RG, Robin NC, Dawson DW, Moon RT, Chien AJ. Wnt/β-catenin signaling and AXIN1 regulate apoptosis triggered by inhibition of the mutant kinase BRAFV600E in human melanoma. Sci Signal. 2012 Jan 10;5(206):ra3. DOI: 10.1126/scisignal.2002274 External link
4.
Biechele T, Chien A, Moon R, VanHook A. [Podcast: 10 January 2012]. Washington, DC: Sci Signal; 2012. Podcast: 14 min. Available from: http://podcasts.aaas.org/science_signaling/ScienceSignaling_120110.mp3 External link
5.
Jeong WJ, Yoon J, Park JC, Lee SH, Lee SH, Kaduwal S, Kim H, Yoon JB, Choi KY. Ras stabilization through aberrant activation of Wnt/β-catenin signaling promotes intestinal tumorigenesis. Sci Signal. 2012 Apr 10;5(219):ra30. DOI: 10.1126/scisignal.2002242 External link