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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 2  |  Page : 272-277

Targeting the canonical Wnt/β-catenin pathway in cancer radioresistance: Updates on the molecular mechanisms


Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

Date of Web Publication1-Apr-2019

Correspondence Address:
Prof. Xiaoying Xue
Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_421_18

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 > Abstract 


Radiation resistance is an important factor that affects the efficacy of radiotherapy; it could even lead to its failure. In recent years, the relationship between the classical Wnt signaling pathway and radiation resistance has gradually attracted attention from scholars. Although most of the findings are comprehensive, they are fragmented and disorganized. This review explores the relationship between classical Wnt signaling pathways and cancer radiation resistance. Previous literature regarding the classical Wnt signaling pathways and cancer radiation resistance from the past decades had been summarized in this article. Moreover, the molecular mechanisms and functions of the canonical Wnt signaling pathway involved in the formation of radioresistance were systemically analyzed and sorted out. Certain rules and internal relationships among different pathways have been further clarified; this is expected to provide valuable clues for further research. The Wnt/β-catenin pathway is closely associated with the formation of cancer radioresistance, which may be a target for improving the effects of radiotherapy.

Keywords: Cancer, canonical Wnt pathway, radioresistance


How to cite this article:
Yang Y, Zhou H, Zhang G, Xue X. Targeting the canonical Wnt/β-catenin pathway in cancer radioresistance: Updates on the molecular mechanisms. J Can Res Ther 2019;15:272-7

How to cite this URL:
Yang Y, Zhou H, Zhang G, Xue X. Targeting the canonical Wnt/β-catenin pathway in cancer radioresistance: Updates on the molecular mechanisms. J Can Res Ther [serial online] 2019 [cited 2019 Sep 17];15:272-7. Available from: http://www.cancerjournal.net/text.asp?2019/15/2/272/255097




 > Introduction Top


As one of the three commonly used treatments for malignant tumor, radiation therapy plays an increasingly important role in treating multiple solid tumors. The efficacy of radiotherapy, as well as its status among tumor treatments, has been markedly enhanced based on the development of precision radiotherapy technology. However, there are still many restrictions on the effects of radiotherapy, and indubitably, radioresistance is one of the major factors governing these effects. Previous studies have indicated that the formation of radioresistance involves the regulation of apoptotic genes,[1] DNA damage repair capacity,[2] hypoxia,[3] cell cycle state,[4] and changes of several signaling pathways.[5] With the progress in the research regarding radiation resistance, radioresistance-related molecular signaling pathways have attracted an increasing amount of attention from scholars. Among them, the canonical Wnt signal pathway is an active pathway participating in multiple cell functions; its importance has gradually been attached to its relationship with the formation of radioresistance. Aimed at discovering more valuable clues based on the relation between the canonical Wnt signaling pathway and radioresistance, this article summarizes the latest advances in this field, with a profound discussion of the complex interactions between the canonical Wnt pathway and cancer radioresistance.


 > Wnt Signaling Pathway Description Top


Wnt was first discovered from a mouse with breast cancer in 1982 and named as gene Int1, owing to its activation depending on the interaction with the mouse mammary tumor virus.[6] The Wnt family, which comprises of crucial intracellular signal molecules, includes a series of secretory proteins; it functions extensively in cell genesis, growth, differentiation, organ formation, and so on.[7],[8] So far, the human Wnt family is composed of 19 different cysteine-rich glycoproteins acting as ligands for more than 15 receptors or co-receptors.[9] Based on their mode of action in cells or animals, Wnt proteins can be classified into canonical and noncanonical Wnt proteins.[10]

The canonical Wnt signal transduction pathway could be activated through the binding of Wnt proteins (such as Wntl, Wnt3a, Wnt8, and Wntl0b) with transmembrane receptors of the Frizzled family and the LRP5/LRP6 co-receptor. Once stimulated, Frizzled can activate the disheveled protein in the cytoplasm; the latter then activates its downstream factor, GSK-3 β-binding protein (GBP).[11],[12] Moreover, activated GBP can identify and inhibit the phosphorylation of GSK-3 β, which spares β-catenin from being phosphorylated. Consequently, β-catenin is accumulated largely in the cytoplasm; it then enters the cell nucleus.[13] Consequently, intranuclear β-catenin binds with the transcription factor (lymphoid enhancer factor/T cell factor [LEF/TCF]) family, the Legless proteins (BCL9 and BCL9L), and PYGO to form a complex, the TCF/LEF-β-catenin-Legless-PYGO complex. Finally, this complex can initiate downstream target genes, including fibroblast growth factor 20 (FGF20), cyclin D1, oncogene (c-Myc), and Wnt-inducible secreted protein-1 (WISP-1), which initiates several rounds of biological changes in cells. This is the process by which β-catenin aggregates target genes and then regulates the cascade reaction.[14] Therefore, Wnts are the key extracellular regulators of β-catenin stabilization, and β-catenin is considered a crucial downstream regulator in the canonical Wnt signaling pathway.[12]

The activation of the noncanonical Wnt signal transduction pathway does not depend on β-catenin, which is usually initiated by Wnt5a and Wnt11.[13] These pathways include the planar cell polarity (PCP) pathway and the calcium pathway, which is initiated through the ROR and different Wnt/FZD bindings and Ryk receptors. The calcium pathway contributes to the activation of Ca2+/CaMKII, cell adhesion, NFAT, and CREB. The activation of the PCP pathway involves molecules such as Rac, RhoA, GTPases, and those from the JNK cascade.[15],[16] Thus, the noncanonical Wnt pathway plays an important regulatory role in cell polarity construction, cytoskeleton rearrangement, and cell movement and adhesion; however, there is a lack of research regarding the involvement of the noncanonical Wnt pathway in tumors.[17],[18]


 > The Canonical Wnt Signaling Pathway Is Involved in the Formation of Tumor Radioresistance Top


Radioresistance, the major cause of radiotherapy failure, has attracted major attention. Recently, a close connection between canonical Wnt pathway and radioresistance has been highly focused upon; this has become an advanced research hotspot. Numerous researches have indicated that the Wnt/β-catenin pathway participates in radiation resistance regulation by affecting tumor cell cycle, cell proliferation, DNA damage repair, and cell apoptosis and invasion.


 > Cell Cycle Top


Cells in various cell cycle stages show different sensitivities to radiotherapy. In general, G2/M-stage cells are most sensitive to radiation, followed by G0/G1-stage cells, whereas S-stage cells develop the greatest resistance to radiation. Cancer cells at a quiescent stage may be the arch criminals for radioresistance and recurrence after radiotherapy.[19] Xue et al.[20] have found that peroxisome proliferator-activated receptor α (PPARα) is overexpressed in pancreatic cancer tissues, and that the PPARα expression level is inversely associated with higher overall patient survival rate. They further observed that PPARα activation by its agonist clofibrate sensitizes pancreatic cancer cells to radiation by upregulating Wnt8a, thereby modulating cell cycle progression and apoptosis in several pancreatic cancer cell lines through the Wnt/β-catenin pathway. Zhang et al.[21] tested the effects of a novel small-molecule inhibitor BC-23 (C21H14 ClN3O4S), which targets β-catenin/Tcf4 on the non-small cell lung cancer cell lines H1299 and H1975. It was found that the inhibitor effectively suppressed the canonical Wnt pathway, downregulated the c-Myc and cyclin D1 expression, and then reduced the population of S-stage cells, the most radioresistant cells, thus improving radiosensitivity. Therefore, the Wnt/β-catenin signaling pathway may be involved in the redistribution of tumor cell cycle, which consequently enhances radioresistance.


 > Cell Proliferation Top


Abnormal cell proliferation exists in almost all cancers; it is vital information for the clinical evaluation of the malignant degree and behavior of cancers. Besides, the accelerated re-proliferation of cancer cells is a critical cause of radioresistance formation.[22] Su et al.[23] and Li et al.[24] found that, compared to KYSE-150 cells, cells from the radioresistant cell line KYSE-150R showed a stronger proliferation ability; in addition, the KYSE-150R cells showed a marked upregulation of the expression of canonical Wnt signaling pathway-related genes, among which, β-catenin upregulation led to the elevated expression levels of the downstream proteins cyclin D1 and Wnt-induced secretory protein 1 (WISP1). Moreover, Li et al.[24] had verified that radioresistant esophageal cancer cells showed stronger proliferation and tumorigenic abilities in mice, and this in vivo experiment revealed that the activation of the canonical Wnt pathway accelerated the proliferation of cells from the radioresistant esophageal cancer strain KYSE-150R. Che et al.[25] studied the radiosensitization effect of the cyclooxygenase-2 (COX-2) inhibitor NS398 (p-methyl sulfobenzene-cyclo-ethyl ether) on the radioresistant esophageal cancer cell line Eca109R50 Gy and discovered that Eca109R50 Gy cells showed certain stem cell properties. Moreover, these cells displayed higher proliferation and colony-forming abilities. In addition, the application of NS398 could enhance the radiosensitivity of Eca109R50 Gy cells, along with the downregulation of the expression of β-catenin and its downstream target gene COX-2. It was speculated that NS398 might enhance radiosensitivity by suppressing the canonical Wnt signaling pathway. Yin et al.[26] constructed a mouse tumor model with three triple-negative breast cancer cells MDA-MB-231, proving that niclosamide can inhibit the expression of Wnt3a by blocking the Wnt/β-catenin signaling pathway, to promote tumor growth and improve the radiosensitivity. Wang et al.[27] demonstrated that cyclophilin A promotes glioma-initiating cell stemness, self-renewal, proliferation, and radiotherapy resistance by binding to β-catenin and is recruited to the Wnt target gene promoters. Wu et al.[28] indicated that thyroid cancer 1 (TC-1) knockout in the human non-small cell lung cancer cell line A549 combined with radiation could distinctly inhibit the canonical Wnt pathway. Meanwhile, the expression of c-Myc, c-met, and cyclin D1, the target genes of that pathway, was downregulated, along with markedly reduced cell proliferation. This proved that TC-1 could affect the radioresistance of lung cancer cells through the canonical Wnt signaling pathway. Su et al.[29] suggested that specific β-catenin/TCF inhibitors could remarkably downregulate the radioresistance of cells from the radioresistant esophageal squamous carcinoma cell line KYSE-150R, by specifically blocking the expression of the downstream proteins CTNNB1 and cyclin D1. Furthermore, it could suppress the proliferative activity of A549 cells and increase the radiosensitivity.


 > Dna Damage Repair Top


DNA double-strand break (DSB) is the most severe type of molecular injury in cells induced by ionization, which is also the direct reason for radiation-induced cell apoptosis. Moreover, DNA DSB residues are important molecular markers for determining cell radiosensitivity.[30] Jun et al.[31] found that, among the numerous DNA repair genes, activation of the Wnt/β-catenin signal transduction pathway can upregulate the expression of DNA ligase 4 (LIG4) in human colorectal cancer. Besides, LIG4 expression was regulated by β-catenin, and the upregulation of LIG4 was closely related to radioresistance in human colorectal cancer cells. In addition, its mechanism might be related to the fact that LIG4 could enhance the nonhomologous end-joining repair capacity of DNA DSBs. Conversely, blocking LIG4 expression could boost the radiosensitivity of human colorectal cancer cells. By using siRNA and silenced expression of the β-catenin protein, Chang et al.[32] conducted RNA interference on the radioresistant human laryngeal cancer cell line AMC-HN-9. They discovered that β-catenin silencing in cells from the laryngeal cancer cell line AMC-HN-9 remarkably reduced radioresistance after radiation compared to the control group. Meanwhile, the expression of Ku70/80, which is considered as the DNA damage repair initiator, was markedly decreased in β-catenin-silenced AMC-HN-9 cells after radiation. In addition, silencing the β-catenin protein activated LKB1/AMPK. Therefore, researchers had speculated that the LKB1/AMPK signaling pathway might be involved in mediating the Wnt/β-catenin pathway and KU70/Ku80 DNA damage repair mechanism. Zhang et al.[33] claimed that WISP1 was a critical downstream target gene of the canonical Wnt signaling pathway; WISP1 is considered a prognostic indicator for esophageal cancer after radiotherapy. Moreover, gain- and loss-of-function experiments have proven that WISP1 mediates radioresistance in both esophageal squamous carcinoma cells and nude-mouse transplanted tumor models. Besides, further research has found that ionizing radiation-induced DNA DSBs could lead to rapid phosphorylation of histone H2AX. However, WISP1 could reverse this process and directly render the phosphorylated histone 2 (γ-H2AX) dephosphorylated, thus maintaining its functions on signal and protein aggregation repair and DNA repair. Therefore, it was concluded that WISP1 participated in DNA damage repair after the activation of the canonical Wnt signaling pathway and, was thus, involved in the formation of radioresistance in esophageal cancer. Su et al.[29] confirmed that FH535 could downregulate the expression of the target gene cyclin D1, weaken its DNA damage repair capacity, and enhance its radiosensitivity by blocking the canonical Wnt signaling pathway. The above research has suggested that the activation of the canonical Wnt signaling pathway in tumor cells may enhance the DNA damage repair capacity by upregulating the expression of LIG4, Ku70/80, and WISP1, consequently inducing radioresistance.


 > Cell Apoptosis Top


It is generally believed that an increase in apoptotic response reveals higher radiosensitivity in cells; it is accompanied with the increase in cell sensitivity. Therefore, some scholars consider the induced apoptotic level as an indicator for measuring tumor radiosensitivity.[34] Tian et al.[35] found that, when the cells from the liver cancer cell line HepG2 were treated with LGK-974, which inhibits Wnt signaling pathways by blocking the secretion of the Wnt3A protein in HepG2 cells, they underwent apoptosis more frequently and grew less rapidly. An enhanced sensitivity to radiation was observed with increasing LGK-974 concentrations. Results showed that inhibiting Wnt3A secretion blocked the canonical Wnt signaling pathway. Using the expression profile analysis, Wang et al.[36] discovered that, compared with carcinoma cells and tissues, lincRNA-p21 expression in colorectal cancer cells and tissues had been downregulated, accompanied with an increased β-catenin expression. In addition, it has been also found that lincRNA-p21 expression is upregulated in colorectal cancer cells receiving X-ray radiation. LincRNA-p21 overexpression increases apoptosis, thereby enhancing the radiosensitivity. Moreover, further research has suggested that lincRNA-p21 overexpression can inhibit β-catenin expression, block the canonical Wnt pathway, and reduce the expression of β-catenin, as well as the downstream target genes c-Myc and cyclin D1. It can simultaneously enhance radiosensitivity by promoting cell apoptosis. Wu et al.[28] found that, after knocking out TC-1 in A549 cells, radiation treatment downregulated the expression of target genes c-Myc, c-met, and cyclin D1, as the canonical Wnt pathway had been distinctly inhibited. It had not only inhibited tumor cell proliferation, but also increased cell apoptosis. Yin et al.[26] found that niclosamide can inhibit Wnt3a expression in MDA-MB-231 cells by blocking the Wnt/β-catenin signaling pathway, promoting tumor cell apoptosis and improving radiosensitivity. The above research proves that activation of the canonical Wnt signaling pathway can induce radioresistance by reducing tumor cell apoptosis. However, the precise molecular mechanism by which it participates in the apoptotic process remains unknown.


 > Cell Invasion and Metastasis Top


Ionizing radiation can increase metastasis by changing the tumor cell phenotype or tumor microenvironment and enhancing the invasion ability of residual tumors.[37] Liu et al.[38] claimed that upregulating the expression of Wnt2B, which promotes invasion and metastasis through the canonical Wnt pathway, by the inhibition of miR-185-3p, could be reversed through the silencing of WNT2B in the nasopharyngeal carcinoma (NPC) cell line 5–8F. Dong et al.[39] found that the invasion capacity of the human glioma cell line U87 was enhanced after irradiation of 3 Gy, while β-catenin/Tcf shows an increased expression and is accumulated in the nucleus. After irradiation, U87 cells showed an activation of the Wnt/β-catenin signaling pathway, as detected by the TOP/FOP luciferase test, while the expression of its target genes, mmp-2 and mmp-9, was upregulated. XAV 939, which antagonizes Wnt signaling by accelerating β-catenin degradation and stabilizing axin, can inhibit the expression of β-catenin, mmp-2, and mmp-9; it then significantly inhibits cell invasion. Therefore, it is believed that the canonical Wnt pathway can induce the invasion and radioresistance of tumor cells. Li et al.[40] found that the expression of miR-185-3p and Wnt2B showed an inverse correlation in NPC cells and tissues. However, in the NPC cell lines CNE-2 and 5-8F, miR-185-3p can inhibit the Wnt2B expression, block the classic Wnt pathways, and enhance the expression of its downstream genes β-catenin, GSK-3 β, and c-Myc. Li also confirmed that Wnt2B/β-catenin signaling pathways activated the epithelial–mesenchymal transition (EMT) in NPC cells and enhanced the metastasis and radioresistance of the tumor cells. He believes that mir-185-3p can affect the radioresistance of NPC cells by regulating Wnt2B. In addition, in their subsequent studies, the group again demonstrated that mir-185-3p could modulate Wnt2B expression and influence tumor cell invasion and metastasis through the classical Wnt pathway. Therefore, it can be considered that the activation of the classical Wnt signaling pathway may induce the invasion and metastasis of certain tumor cells, be related with their EMT, and then decrease the effect of radiotherapy.


 > Cell Differentiation Top


The presence of a heterogeneous subgroup of tumor cell population with poor radiotherapy sensitivity is one of the most important causes for the relatively high local recurrence and/or distant metastasis rate after radiotherapy.[41] Cojoc et al.[42] demonstrated that prostate cancer cells with positive acetaldehyde dehydrogenase (ALDH) expression harbored radiotherapy resistance; the ALDH expression was regulated by the β-catenin/TCF transcriptional complex. Activation of the canonical Wnt pathway could upregulate ALDH expression, accompanied by the EMT of tumor cells and enhanced repair capacity following DNA damage, subsequently increasing the radioresistance of tumor cells. The number of ALDH (+) cells decreased after the canonical Wnt signaling pathway was blocked, along with decreased radioresistance. Therefore, ALDH is considered as an index for evaluating prostate cancer radioresistance. Li et al.[43] conducted gene expression profiling on a radioresistant esophageal cancer cell line induced by repeated X-ray exposure. They found that the miR-21 expression increased in these cells, accompanied by the activation of the Wnt/β-catenin signaling pathway and upregulation of β-catenin expression, which together induce tumor radioresistance by regulating cell apoptosis and proliferation. To further investigate the effect of miR-21 downregulation on the radiosensitivity of esophageal cancer cells, the esophageal cancer cell line TE-1 with stable miR-21 downregulation was successfully constructed. Consequently, miR-21 downregulation could enhance the radiosensitivity of TE-1 cells, which might be due to the decreased activation of the Wnt/β-catenin signaling pathway, reduced β-catenin expression, and decreased proportion of p75NTR+ cells. Currently, research concerning the association between the canonical Wnt signaling pathway, cell differentiation, and radioresistance is limited. It is currently acknowledged that the activation of the canonical Wnt signaling pathway can promote tumor cell differentiation, and simultaneously contribute to radioresistance by affecting the EMT of tumor cells, repair capacity of tumor cells after DNA damage, and tumor cell apoptosis and proliferation. Hence, whether cell differentiation serves as an independent factor mediating radioresistance warrants further investigation.


 > Correlation of the Molecular Mechanism and Cell Function Top


At present, the complicated mechanism by which the canonical Wnt signaling pathway is involved in radioresistance remains unclear. It is a complicated network, including changes in cell cycle, cell proliferation, repair capacity following DNA damage, cell apoptosis, invasion, and metastasis, all of which coordinate with each other to exert their effects on radioresistance. Their interactions can be summarized as follows:First, the research mainly focuses on changes in β-catenin as well as its downstream signal proteins, such as TCF/LEF, c-Myc, cyclin D1, and WISP1. Second, the same target gene may affect radioresistance through different mechanisms. For instance, cyclin D1 is associated with cell cycle, proliferation, and apoptosis; c-Myc is correlated with cell cycle, apoptosis, invasion, and metastasis, while COX-2 is related to cell proliferation. Third, genes of the canonical Wnt pathway can participate in radioresistance by affecting other genes or pathways. For instance, β-catenin can regulate LIG4 expression; WISP1 can directly dephosphorylate the phosphorylated histone 2 (γ-H2AX); β-catenin/TCF transcriptional complex can regulate ALDH expression; and LIG4, γ-H2AX, and ALDH can contribute to radioresistance by enhancing repair capacity following DNA damage, while the LKB1/AMPK signaling pathway may participate in damage repair following DNA damage by mediating the Wnt/β-catenin pathway and KU70/Ku80 expression [Figure 1]. In this article, we have mainly reviewed the mechanism of the activated Wnt/β-catenin signaling pathway in the formation of radioresistance. However, the regulatory mechanism of Wnt is complicated. Zhou et al.[44] demonstrated that NRAGE activated the canonical Wnt pathway by mediating the nuclear translocation of β-catenin through its subcellular localization changes, subsequently promoting the formation of radioresistance in esophageal cancer. Yang et al.[45] found that the miR-146b-5p/HuR/lincRNA-p21/β-catenin signaling pathway could enhance the radioresistance of glioma stem cells. Therefore, great efforts should be made to thoroughly illustrate the mechanism by which the canonical Wnt pathway affects radioresistance. The extensive application of gene chip, protein chip, gene sequencing, and mass-spectrometric techniques has given rise to the possibility of discovering the differential upstream genes or proteins of the Wnt pathway or signaling pathways associated with Wnt pathways through screening big data,[46],[47],[48],[49] which will further reveal the role of the canonical Wnt pathway in the formation of tumor radioresistance.
Figure 1: Role of the canonical Wnt pathway in the information of tumor radiation resistances

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 > Conclusion and Prospect Top


The existence of radioresistance is an important restricted factor for the efficacy of radiotherapy; moreover, the Wnt/β-catenin pathway is closely associated with the formation of tumor radioresistance. Therefore, studies on the relationship between the canonical Wnt pathway and radiation resistance could improve the curative effect of radiotherapy at the molecular level. We can detect the expression of canonical Wnt pathway-related markers to predict radiotherapy efficacy and improve the treatment accuracy. In addition, we can eventually identify potential canonical Wnt signaling pathway radiotherapy sensitizers to enhance radiotherapy efficacy. Therefore, due to the favorable clinical significances, it is still very meaningful to explore the relationship between the canonical Wnt signaling pathway and tumor radioresistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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