Targeting Wnt Signaling through Small molecules in Governing Stem Cell Fate and Diseases

Author(s): Antara Banerjee*, Ganesan Jothimani, Suhanya Veronica Prasad, Francesco Marotta, Surajit Pathak

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 19 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: The conserved Wnt/β-catenin signaling pathway is responsible for multiple functions including regulation of stem cell pluripotency, cell migration, self-renewability and cell fate determination. This signaling pathway is of utmost importance, owing to its ability to fuel tissue repair and regeneration of stem cell activity in diverse organs. The human adult stem cells including hematopoietic cells, intestinal cells, mammary and mesenchymal cells rely on the manifold effects of Wnt pathway. The consequences of any dysfunction or manipulation in the Wnt genes or Wnt pathway components result in specific developmental defects and may even lead to cancer, as it is often implicated in stem cell control. It is absolutely essential to possess a comprehensive understanding of the inhibition and/ or stimulation of the Wnt signaling pathway which in turn is implicated in determining the fate of the stem cells.

Results: In recent years, there has been considerable interest in the studies associated with the implementation of small molecule compounds in key areas of stem cell biology including regeneration differentiation, proliferation. In support of this statement, small molecules have unfolded as imperative tools to selectively activate and inhibit specific developmental signaling pathways involving the less complex mechanism of action. These compounds have been reported to modulate the core molecular mechanisms by which the stem cells regenerate and differentiate.

Conclusion: This review aims to provide an overview of the prevalent trends in the small molecules based regulation of stem cell fate via targeting the Wnt signaling pathway.

Keywords: Wnt ligands, Wnt inhibitors, Wnt activators, leukemia, alzheimer, progenitor cells, DCA, quercetin, XAV939, pyrvinium.

Nusse, R.; Varmus, H. Three decades of Wnts: A personal perspective on how a scientific field developed. EMBO J., 2012, 31(12), 2670-2684.
Chambers, I.; Colby, D.; Robertson, M.; Nichols, J.; Lee, S.; Tweedie, S.; Smith, A. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell, 2003, 113(5), 643-655.
Reya, T.; Duncan, A.W.; Ailles, L.; Domen, J.; Scherer, D.C.; Willert, K.; Hintz, L.; Nusse, R.; Weissman, I.L. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature, 2003, 423(6938), 409-414.
Korvala, J.; Jüppner, H.; Mäkitie, O.; Sochett, E.; Schnabel, D.; Mora, S.; Bartels, C.F.; Warman, M.L.; Deraska, D.; Cole, W.G.; Hartikka, H.; Ala-Kokko, L.; Männikkö, M. Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity. BMC Med. Genet., 2012, 13, 26.
Gokhale, A.G.; Chelluri, L.K.; Kumaresan, K.; Subramanyam, G.; Sudhakar, K.; Vemuri, S.; Debnath, T.; Ratnakar, K.S. Evaluation of the autologous bone marrow mononuclear therapy and functional restoration in the scarred myocardium by imaging analysis. J. Cardiovasc. Dis. Res., 2011, 2(2), 133-136.
Polakis, P. The many ways of Wnt in cancer. Curr. Opin. Genet. Dev., 2007, 17(1), 45-51.
Sugimura, R.; He, X.C.; Venkatraman, A.; Arai, F.; Box, A.; Semerad, C.; Haug, J.S.; Peng, L.; Zhong, X.B.; Suda, T.; Li, L. Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. Cell, 2012, 150(2), 351-365.
Ng, A.P.; Alexander, W.S. Haematopoietic stem cells: Past, present and future. Cell Death Discov., 2017, 3, 17002.
Lento, W.; Congdon, K.; Voermans, C.; Kritzik, M.; Reya, T. Wnt signaling in normal and malignant hematopoiesis. Cold Spring Harb. Perspect. Biol., 2013, 5(2), a008011.
Van Den Berg, D.J.; Sharma, A.K.; Bruno, E.; Hoffman, R. Role of members of the Wnt gene family in human hematopoiesis. Blood, 1998, 92(9), 3189-3202.
Corrigan, P.M.; Dobbin, E.; Freeburn, R.W.; Wheadon, H. Patterns of Wnt/Fzd/LRP gene expression during embryonic hematopoiesis. Stem Cells Dev., 2009, 18(5), 759-772.
Goessling, W.; North, T.E.; Loewer, S.; Lord, A.M.; Lee, S.; Stoick-Cooper, C.L.; Weidinger, G.; Puder, M.; Daley, G.Q.; Moon, R.T.; Zon, L.I. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell, 2009, 136(6), 1136-1147.
Mulroy, T.; McMahon, J.A.; Burakoff, S.J.; McMahon, A.P.; Sen, J. Wnt-1 and Wnt-4 regulate thymic cellularity. Eur. J. Immunol., 2002, 32(4), 967-971.
Fleming, H.E.; Janzen, V.; Lo Celso, C.; Guo, J.; Leahy, K.M.; Kronenberg, H.M.; Scadden, D.T. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell, 2008, 2(3), 274-283.
Tarafdar, A.; Dobbin, E.; Corrigan, P.; Freeburn, R.; Wheadon, H. Canonical Wnt signaling promotes early hematopoietic progenitor formation and erythroid specification during embryonic stem cell differentiation. PLoS One, 2013, 8(11), e81030.
Machon, O.; Backman, M.; Machonova, O.; Kozmik, Z.; Vacik, T.; Andersen, L.; Krauss, S. A dynamic gradient of Wnt signaling controls initiation of neurogenesis in the mammalian cortex and cellular specification in the hippocampus. Dev. Biol., 2007, 311(1), 223-237.
Inestrosa, N.C.; Arenas, E. Emerging roles of Wnts in the adult nervous system. Nat. Rev. Neurosci., 2010, 11(2), 77-86.
L’episcopo, F.; Serapide, M.F.; Tirolo, C.; Testa, N.; Caniglia, S.; Morale, M.C.; Pluchino, S.; Marchetti, B.A. Wnt1 regulated Frizzled-1/β-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection. Mol. Neurodegener., 2011, 6, 49.
Beghini, A.; Corlazzoli, F.; Del Giacco, L.; Re, M.; Lazzaroni, F.; Brioschi, M.; Valentini, G.; Ferrazzi, F.; Ghilardi, A.; Righi, M.; Turrini, M.; Mignardi, M.; Cesana, C.; Bronte, V.; Nilsson, M.; Morra, E.; Cairoli, R. Regeneration-associated WNT signaling is activated in long-term reconstituting AC133bright acute myeloid leukemia cells. Neoplasia, 2012, 14(12), 1236-1248.
Janovska, P.; Poppova, L.; Plevova, K.; Plesingerova, H.; Behal, M.; Kaucka, M.; Ovesna, P.; Hlozkova, M.; Borsky, M.; Stehlikova, O.; Brychtova, Y.; Doubek, M.; Machalova, M.; Baskar, S.; Kozubik, A.; Pospisilova, S.; Pavlova, S.; Bryja, V. Autocrine signaling by Wnt-5a deregulates chemotaxis of leukemic cells and predicts clinical outcome in chronic lymphocytic leukemia. Clin. Cancer Res., 2016, 22(2), 459-469.
Metzeler, K.H.; Heilmeier, B.; Edmaier, K.E.; Rawat, V.P.; Dufour, A.; Döhner, K.; Feuring-Buske, M.; Braess, J.; Spiekermann, K.; Büchner, T.; Sauerland, M.C.; Döhner, H.; Hiddemann, W.; Bohlander, S.K.; Schlenk, R.F.; Bullinger, L.; Buske, C. High expression of lymphoid enhancer-binding factor-1 (LEF1) is a novel favorable prognostic factor in cytogenetically normal acute myeloid leukemia. Blood, 2012, 120(10), 2118-2126.
Tickenbrock, L.; Schwäble, J.; Wiedehage, M.; Steffen, B.; Sargin, B.; Choudhary, C.; Brandts, C.; Berdel, W.E.; Müller-Tidow, C.; Serve, H. Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction. Blood, 2005, 105(9), 3699-3706.
Selkoe, D.; Mandelkow, E.; Holtzman, D. Deciphering Alzheimer disease. Cold Spring Harb. Perspect. Med., 2012, 2(1), a011460.
Cerpa, W.; Godoy, J.A.; Alfaro, I.; Farías, G.G.; Metcalfe, M.J.; Fuentealba, R.; Bonansco, C.; Inestrosa, N.C. Wnt-7a modulates the synaptic vesicle cycle and synaptic transmission in hippocampal neurons. J. Biol. Chem., 2008, 283(9), 5918-5927.
Ahmad-Annuar, A.; Ciani, L.; Simeonidis, I.; Herreros, J.; Fredj, N.B.; Rosso, S.B.; Hall, A.; Brickley, S.; Salinas, P.C. Signaling across the synapse: A role for Wnt and Dishevelled in presynaptic assembly and neurotransmitter release. J. Cell Biol., 2006, 174(1), 127-139.
Varela-Nallar, L.; Grabowski, C.P.; Alfaro, I.E.; Alvarez, A.R.; Inestrosa, N.C. Role of the Wnt receptor Frizzled-1 in presynaptic differentiation and function. Neural Dev., 2009, 4, 41.
Surmann-Schmitt, C.; Widmann, N.; Dietz, U.; Saeger, B.; Eitzinger, N.; Nakamura, Y.; Rattel, M.; Latham, R.; Hartmann, C.; von der Mark, H.; Schett, G.; von der Mark, K.; Stock, M. Wif-1 is expressed at cartilage-mesenchyme interfaces and impedes Wnt3a-mediated inhibition of chondrogenesis. J. Cell Sci., 2009, 122(Pt 20), 3627-3637.
Suzuki, H.; Gabrielson, E.; Chen, W.; Anbazhagan, R.; van Engeland, M.; Weijenberg, M.P.; Herman, J.G.; Baylin, S.B. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat. Genet., 2002, 31(2), 141-149.
Takada, T.; Yagi, Y.; Maekita, T.; Imura, M.; Nakagawa, S.; Tsao, S.W.; Miyamoto, K.; Yoshino, O.; Yasugi, T.; Taketani, Y.; Ushijima, T. Methylation-associated silencing of the Wnt antagonist SFRP1 gene in human ovarian cancers. Cancer Sci., 2004, 95(9), 741-744.
Stoehr, R.; Wissmann, C.; Suzuki, H.; Knuechel, R.; Krieg, R.C.; Klopocki, E.; Dahl, E.; Wild, P.; Blaszyk, H.; Sauter, G.; Simon, R.; Schmitt, R.; Zaak, D.; Hofstaedter, F.; Rosenthal, A.; Baylin, S.B.; Pilarsky, C.; Hartmann, A. Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer. Lab. Invest., 2004, 84(4), 465-478.
Fukui, T.; Kondo, M.; Ito, G.; Maeda, O.; Sato, N.; Yoshioka, H.; Yokoi, K.; Ueda, Y.; Shimokata, K.; Sekido, Y. Transcriptional silencing of secreted frizzled related protein 1 (SFRP 1) by promoter hypermethylation in non-small-cell lung cancer. Oncogene, 2005, 24(41), 6323-6327.
Huang, S.M.; Mishina, Y.M.; Liu, S.; Cheung, A.; Stegmeier, F.; Michaud, G.A.; Charlat, O.; Wiellette, E.; Zhang, Y.; Wiessner, S.; Hild, M.; Shi, X.; Wilson, C.J.; Mickanin, C.; Myer, V.; Fazal, A.; Tomlinson, R.; Serluca, F.; Shao, W.; Cheng, H.; Shultz, M.; Rau, C.; Schirle, M.; Schlegl, J.; Ghidelli, S.; Fawell, S.; Lu, C.; Curtis, D.; Kirschner, M.W.; Lengauer, C.; Finan, P.M.; Tallarico, J.A.; Bouwmeester, T.; Porter, J.A.; Bauer, A.; Cong, F. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature, 2009, 461(7264), 614-620.
Nicoleau, C.; Varela, C.; Bonnefond, C.; Maury, Y.; Bugi, A.; Aubry, L.; Viegas, P.; Bourgois-Rocha, F.; Peschanski, M.; Perrier, A.L. Embryonic stem cells neural differentiation qualifies the role of Wnt/β-Catenin signals in human telencephalic specification and regionalization. Stem Cells, 2013, 31(9), 1763-1774.
Thorne, C.A.; Hanson, A.J.; Schneider, J.; Tahinci, E.; Orton, D.; Cselenyi, C.S.; Jernigan, K.K.; Meyers, K.C.; Hang, B.I.; Waterson, A.G.; Kim, K.; Melancon, B.; Ghidu, V.P.; Sulikowski, G.A.; LaFleur, B.; Salic, A.; Lee, L.A.; Miller, D.M.; Lee, E. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat. Chem. Biol., 2010, 6(11), 829-836.
Lian, X.; Zhang, J.; Azarin, S.M.; Zhu, K.; Hazeltine, L.B.; Bao, X.; Hsiao, C.; Kamp, T.J.; Palecek, S.P. Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions. Nat. Protoc., 2013, 8(1), 162-175.
Chen, B.; Dodge, M.E.; Tang, W.; Lu, J.; Ma, Z.; Fan, C.W.; Wei, S.; Hao, W.; Kilgore, J.; Williams, N.S.; Roth, M.G.; Amatruda, J.F.; Chen, C.; Lum, L. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat. Chem. Biol., 2009, 5(2), 100-107.
Li, Y.; Li, P.K.; Roberts, M.J.; Arend, R.C.; Samant, R.S.; Buchsbaum, D.J. Multi-targeted therapy of cancer by niclosamide: A new application for an old drug. Cancer Lett., 2014, 349(1), 8-14.
Proffitt, K.D.; Madan, B.; Ke, Z.; Pendharkar, V.; Ding, L.; Lee, M.A.; Hannoush, R.N.; Virshup, D.M. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res., 2013, 73(2), 502-507.
Boulter, L.; Guest, R.V.; Kendall, T.J.; Wilson, D.H.; Wojtacha, D.; Robson, A.J.; Ridgway, R.A.; Samuel, K.; Van Rooijen, N.; Barry, S.T.; Wigmore, S.J.; Sansom, O.J.; Forbes, S.J. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J. Clin. Invest., 2015, 125(3), 1269-1285.
Chen, Z.; Venkatesan, A.M.; Dehnhardt, C.M.; Dos Santos, O.; Delos Santos, E.; Ayral-Kaloustian, S.; Chen, L.; Geng, Y.; Arndt, K.T.; Lucas, J.; Chaudhary, I.; Mansour, T.S. 2,4-Diamino-quinazolines as inhibitors of beta-catenin/Tcf-4 pathway: Potential treatment for colorectal cancer. Bioorg. Med. Chem. Lett., 2009, 19(17), 4980-4983.
Tarapore, R.S.; Siddiqui, I.A.; Mukhtar, H. Modulation of Wnt/β-catenin signaling pathway by bioactive food components. Carcinogenesis, 2012, 33(3), 483-491.
Park, C.H.; Chang, J.Y.; Hahm, E.R.; Park, S.; Kim, H.K.; Yang, C.H. Quercetin, a potent inhibitor against beta-catenin/Tcf signaling in SW480 colon cancer cells. Biochem. Biophys. Res. Commun., 2005, 328(1), 227-234.
Mojsin, M.; Vicentic, J.M.; Schwirtlich, M.; Topalovic, V.; Stevanovic, M. Quercetin reduces pluripotency, migration and adhesion of human teratocarcinoma cell line NT2/D1 by inhibiting Wnt/β-catenin signaling. Food Funct., 2014, 5(10), 2564-2573.
Tzeng, H.E.; Yang, L.; Chen, K.; Wang, Y.; Liu, Y.R.; Pan, S.L.; Gaur, S.; Hu, S.; Yen, Y. The pan-PI3K inhibitor GDC-0941 activates canonical WNT signaling to confer resistance in TNBC cells: Rresistance reversal with WNT inhibitor. Oncotarget, 2015, 6(13), 11061-11073.
Morrell, N.T.; Leucht, P.; Zhao, L.; Kim, J.B.; ten Berge, D.; Ponnusamy, K.; Carre, A.L.; Dudek, H.; Zachlederova, M.; McElhaney, M.; Brunton, S.; Gunzner, J.; Callow, M.; Polakis, P.; Costa, M.; Zhang, X.M.; Helms, J.A.; Nusse, R. Liposomal packaging generates Wnt protein with in vivo biological activity. PLoS One, 2008, 3(8), e2930.
Cruciat, C.M.; Ohkawara, B.; Acebron, S.P.; Karaulanov, E.; Reinhard, C.; Ingelfinger, D.; Boutros, M.; Niehrs, C. Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science, 2010, 327(5964), 459-463.
Lau, T.; Chan, E.; Callow, M.; Waaler, J.; Boggs, J.; Blake, R.A.; Magnuson, S.; Sambrone, A.; Schutten, M.; Firestein, R.; Machon, O.; Korinek, V.; Choo, E.; Diaz, D.; Merchant, M.; Polakis, P.; Holsworth, D.D.; Krauss, S.; Costa, M. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res., 2013, 73(10), 3132-3144.
Shan, J.; Shi, D.L.; Wang, J.; Zheng, J. Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry, 2005, 44(47), 15495-15503.
Emami, K.H.; Nguyen, C.; Ma, H.; Kim, D.H.; Jeong, K.W.; Eguchi, M.; Moon, R.T.; Teo, J.L.; Oh, S.W.; Kim, H.Y.; Moon, S.H.; Ha, J.R.; Kahn, M. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc. Natl. Acad. Sci. USA, 2004, 101(34), 12682-12687.
Lepourcelet, M.; Chen, Y.N.; France, D.S.; Wang, H.; Crews, P.; Petersen, F.; Bruseo, C.; Wood, A.W.; Shivdasani, R.A. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell, 2004, 5(1), 91-102.
Fiskus, W.; Sharma, S.; Saha, S.; Shah, B.; Devaraj, S.G.; Sun, B.; Horrigan, S.; Leveque, C.; Zu, Y.; Iyer, S.; Bhalla, K.N. Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells. Leukemia, 2015, 29(6), 1267-1278.
Tang, L.; Zhu, H.; Yang, X.; Xie, F.; Peng, J.; Jiang, D.; Xie, J.; Qi, M.; Yu, L. Shizukaol, D. A dimeric sesquiterpene isolated from Chloranthus serratus, represses the growth of human liver cancer cells by modulating Wnt signalling pathway. PLoS One, 2016, 11(3), e0152012.
Rattanawarawipa, P.; Pavasant, P.; Osathanon, T.; Sukarawan, W. Effect of lithium chloride on cell proliferation and osteogenic differentiation in stem cells from human exfoliated deciduous teeth. Tissue Cell, 2016, 48(5), 425-431.
Moon, J.S.; Ko, H.M.; Park, J.I.; Kim, J.H.; Kim, S.H.; Kim, M.S. Inhibition of human mesenchymal stem cell proliferation via Wnt signaling activation. J. Cell. Biochem., 2018, 119(2), 1670-1678.
Qi, L.; Tang, Y.; He, W.; Pan, H.; Jiang, W.; Wang, L.; Deng, W. Lithium chloride promotes neuronal differentiation of rat neural stem cells and enhances neural regeneration in Parkinson’s disease model. Cytotechnology, 2017, 69(2), 277-287.
Wu, Y.; Ai, Z.; Yao, K.; Cao, L.; Du, J.; Shi, X.; Guo, Z.; Zhang, Y. CHIR99021 promotes self-renewal of mouse embryonic stem cells by modulation of protein-encoding gene and long intergenic non-coding RNA expression. Exp. Cell Res., 2013, 319(17), 2684-2699.
Sato, N.; Meijer, L.; Skaltsounis, L.; Greengard, P.; Brivanlou, A.H. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat. Med., 2004, 10(1), 55-63.
Tseng, A.S.; Engel, F.B.; Keating, M.T. The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes. Chem. Biol., 2006, 13(9), 957-963.
Bodine, P.V.; Stauffer, B.; Ponce-de-Leon, H.; Bhat, R.A.; Mangine, A.; Seestaller-Wehr, L.M.; Moran, R.A.; Billiard, J.; Fukayama, S.; Komm, B.S.; Pitts, K.; Krishnamurthy, G.; Gopalsamy, A.; Shi, M.; Kern, J.C.; Commons, T.J.; Woodworth, R.P.; Wilson, M.A.; Welmaker, G.S.; Trybulski, E.J.; Moore, W.J. A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation. Bone, 2009, 44(6), 1063-1068.
Pai, R.; Tarnawski, A.S.; Tran, T. Deoxycholic acid activates beta-catenin signaling pathway and increases colon cell cancer growth and invasiveness. Mol. Biol. Cell, 2004, 15(5), 2156-2163.
Miyabayashi, T.; Teo, J.L.; Yamamoto, M.; McMillan, M.; Nguyen, C.; Kahn, M. Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency. Proc. Natl. Acad. Sci. USA, 2007, 104(13), 5668-5673.
Zeng, X.; Tamai, K.; Doble, B.; Li, S.; Huang, H.; Habas, R.; Okamura, H.; Woodgett, J.; He, X. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature, 2005, 438(7069), 873-877.
Atkinson, J.M.; Rank, K.B.; Zeng, Y.; Capen, A.; Yadav, V.; Manro, J.R.; Engler, T.A.; Chedid, M. Activating the Wnt/β-Catenin pathway for the treatment of melanoma--Application of LY2090314, a novel selective inhibitor of glycogen synthase kinase-3. PLoS One, 2015, 10(4), e0125028.
Hernández-Maqueda, J.G.; Luna-Ulloa, L.B.; Santoyo-Ramos, P.; Castañeda-Patlán, M.C.; Robles-Flores, M. Protein kinase C delta negatively modulates canonical Wnt pathway and cell proliferation in colon tumor cell lines. PLoS One, 2013, 8(3), e58540.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [233 - 246]
Pages: 14
DOI: 10.2174/1871530319666190118103907
Price: $65

Article Metrics

PDF: 82
PRC: 2