Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex

Jung and Park Experimental & Molecular Medicine (2020) 52:183–191 https://doi.org/10.1038/s12276-020-0380-6 REVIEW ARTICLE Experimental & Molecular Medicine Open Access Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex Youn-Sang Jung1 and Jae-Il Park 1,2,3 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Abstract Wnt/β-catenin signaling is implicated in many physiological processes, including development, tissue homeostasis, and tissue regeneration. In human cancers, Wnt/β-catenin signaling is highly activated, which has led to the development of various Wnt signaling inhibitors for cancer therapies. Nonetheless, the blockade of Wnt signaling causes side effects such as impairment of tissue homeostasis and regeneration. Recently, several studies have identified cancer-specific Wnt signaling regulators. In this review, we discuss the Wnt inhibitors currently being used in clinical trials and suggest how additional cancer-specific regulators could be utilized to treat Wnt signaling-associated cancer. Introduction Wnt signaling orchestrates various biological processes, such as cell proliferation, differentiation, organogenesis, tissue regeneration, and tumorigenesis1–5. Classically, Wnt signaling is divided into β-catenin-dependent (canonical, Wnt/β-catenin pathway) and β-catenin-independent (noncanonical, Wnt/planar cell polarity [PCP] and calcium pathway) signaling6,7. Canonical Wnt signaling mainly regulates cell proliferation, and noncanonical Wnt signaling controls cell polarity and movement. However, this terminological distinction is unclear, and has been questions by studies proposing the involvement of both β-catenin-dependent and β-cateninindependent Wnt signaling in tumorigenesis8. For instance, APC and β-catenin are not only involved in cell proliferation but have also been linked to cell-to-cell adhesion9. In this review, we will discuss an ongoing effort to inhibit Wnt signaling and suggest potential approaches Correspondence: Jae-Il Park () 1 Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2 Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Full list of author information is available at the end of the article. to target Wnt signaling for cancer therapies proposed from recent studies. Wnt signaling and clinical trials in human cancers β-Catenin is a crucial signaling transducer in Wnt signaling10,11. The β-catenin protein destruction complex composed of adenomatous polyposis coli (APC), casein kinase 1 (CK1), glycogen synthase kinase 3α/β (GSK-3α/β), and AXIN1 tightly controls β-catenin via phosphorylation-mediated proteolysis10,12–16. In this section, we briefly describe how genetic alterations of Wnt signaling contribute to tumorigenesis and introduce recent clinical trials that have aimed to inhibit Wnt signaling for cancer treatment. The β-catenin destruction complex Colorectal cancer (CRC) is the representative of human cancer caused by Wnt signaling hyperactivation17,18. CRC displays a high mutation frequency in APC (~70%)19–21. In 1991, APC mutation was identified as the cause of hereditary colon cancer syndrome, also called familial adenomatous polyposis22. APC forms the β-catenin destruction complex in association with CK1, AXIN1, and GSK-3 and interacts with β-catenin15,23,24. This protein destruction © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Korean Society for Biochemistry and Molecular Biology Jung and Park Experimental & Molecular Medicine (2020) 52:183–191 complex downregulates β-catenin through phosphorylation and ubiquitin-mediated protein degradation10,12–16. Genetic mutations causing the loss of function of the destruction complex or gain of function of β-catenin lead to nuclear translocation of β-catenin, resulting in T-cell factor (TCF)4/ β-catenin-mediated transactivation of Wnt target genes25,26. The Vogelstein group established a multistep tumorigenesis model of CRC. APC mutation is an early event that initiates CRC adenoma27. CRC progression also requires additional genetic alterations in KRAS, PI3K, TGF-β, SMAD4, and TP5327. Moreover, epigenetic silencing of negative regulators of Wnt signaling was also frequently found in the absence of APC mutations28,29. APC is a multifunctional protein. In addition to its role in β-catenin degradation, APC binds to actin and actin-regulating proteins30–33, which controls the interaction between E-cadherin and α-/ β-catenin and various physiological processes, including migration and chromosomal fidelity34–38. Importantly, recent studies revealed that APC mutation is insufficient to fully activate Wnt signaling. Furthermore, even if APC is mutated, mutant APC still negatively regulates β-catenin to some extent39,40, which will be discussed later. AXIN1 is a multidomain scaffolding protein that forms the β-catenin destruction complex in association with APC, CK1, and GSK310,41,42. In human cancer, AXIN1 mutations are scattered throughout the whole coding sequence of the AXIN1 gene43,44, which results in disassembly of the β-catenin destruction complex. As a priming kinase, CK1 initially phosphorylates β-catenin (Ser45), which induces the sequential phosphorylation of β-catenin by GSK3. Subsequently, phosphorylated β-catenin is recognized and degraded by E3 ubiquitin ligase (β-TrCP)10,12–16. GSK3 is a serine/threonine kinase that phosphorylates three serine/threonine residues of β-catenin (Ser33, Ser37, and Thr41)45,46. Since GSK3 does not bind to β-catenin directly, AXIN1 and APC facilitate the interaction of GSK3 with β-catenin47,48. Moreover, unphosphorylated AXIN1 shows a low binding affinity to β-catenin, which is increased by phosphorylation of AXIN1 via GSK3 kinase activity49,50. Low-density lipoprotein receptor-related protein 5/6 (LRP5/6) coreceptor is also phosphorylated by CK1 and GSK3, leading to the recruitment of AXIN1 to the membrane51–53. WNT ligands and receptors Under physiological conditions, (...truncated)