Premise and peril of Wnt signaling activation through GSK-3β inhibition

Law, Samuel M.; Zheng, Jie

doi:10.1016/j.isci.2022.104159

Cited by 43 publications

(20 citation statements)

References 44 publications

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“…These mutations lead to frame shift of UXT-V1 translation, thus creating UXT-V1 knockout cells (KO-1#, KO-2#). Because the GSK3β can recruit β-catenin and promotes its phosphorylation and degradation [27], we want to know whether UXT-V1 played a role in this bio-catalytical process. By using the wildtype and two of UXT-V1 knockout HCT116 cell lines, we observed that the phosphorylated β-catenin levels were increased in two UXT-V1 knockout cells (Fig.…”

Section: Uxt-v1 Regulates Gsk3β Mediated Phosphorylation Of β-Cateninmentioning

confidence: 99%

UXT-V1 contributes to the malignant phenotypes of colorectal cancer via GSK3β by activating Wnt/β-catenin pathway

Chen

Xiao

et al. 2023

Preprint

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Background: Colorectal cancer (CRC) is one of malignant tumors that seriously threatening human health. β-catenin is a central hub in Wnt pathway, aberrant activation of Wnt/β-catenin signaling pathway promotes the tumorigenesis/progression of CRC. Methods and Results: Here we found a β-catenin interactor, UXT-V1, could modulate Wnt signaling. The expression of UXT-V1 mRNA was increased in CRC tissues. Overexpression of UXT-V1 increased the canonical Wnt signaling, as evidenced by Wnt reporter systems and the up-regulation of marker genes including Axin, CyclinD1 and c-Myc. While, knockdown of UXT-V1 impaired the expression of these genes and attenuated Wnt signaling. Mechanistically, overexpression of UXT-V1 could inhibit GSK3β mediated β-catenin phosphorylation and degradation. Knockout of UXT-V1 increased β-catenin phosphorylation, prevented CRC cell growth, and inhibited tumorigenesis in NOD-SCID mice. Conclusions: Taken together, our findings revealed that UXT-V1 could control Wnt signaling through targeting GSK3β mediated β-catenin phosphorylation and degradation, providing a molecular basis for CRC treatment.

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Section: Uxt-v1 Regulates Gsk3β Mediated Phosphorylation Of β-Cateninmentioning

confidence: 99%

UXT-V1 contributes to the malignant phenotypes of colorectal cancer via GSK3β by activating Wnt/β-catenin pathway

Chen

Xiao

et al. 2023

Preprint

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“…Its localization and stability depend on the interaction with GSK-3β/APC/AXIN or TCF/LEF through a competition mechanism. 45 , 46 , 47 , 48 , 49 Herein, we observed that both the total content and the nuclear localization of the β-catenin protein were decreased markedly ( Figures 4 C and 4D), while the level of phosphorylated β-catenin was increased in SOX4-deficient C3H10T1/2 MSCs ( Figure 4 C). Moreover, LEF1 and TCF1, two major transcription factors interacted with β-catenin and initiated the transcription of Wnt target genes in the nucleus, declined sharply after SOX4 depletion ( Figures 4 C and S3 A), while the other Wnt transcriptional factors, TCF3 and TCF4, remained unchanged ( Figures 4 C and S3 A).…”

Section: Resultsmentioning

confidence: 80%

Suppression of preadipocyte determination by SOX4 limits white adipocyte hyperplasia in obesity

He¹,

Wang²,

Li³

et al. 2023

iScience

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“…Enthrallingly, UA attenuated the mRNA levels of some key players of the Wnt/β-catenin signaling axis of SW620 cells, such as Wnt4, β-catenin, TCF4, and LEF1, but heightened GSK-3β mRNA expression (Figure A). GSK-3β can phosphorylate cytoplasmic β-catenin, resulting in the ubiquitin–proteasome system-mediated destruction of β-catenin, conducted by the Axin/GSK-3β/APC-constituted destruction complex . However, phosphorylation of GSK-3β by protein kinase C may abolish GSK-3β′s action of phosphorylating β-catenin, leading to the cytoplasmic increase of β-catenin and its nuclear translocation, where β-catenin, together with TCF4 and LEF1, transactivates target gene transcription, e.g., oncogenic c-Myc and cyclin D1 .…”

Section: Resultsmentioning

confidence: 99%

“…GSK-3β can phosphorylate cytoplasmic β-catenin, resulting in the ubiquitin−proteasome system-mediated destruction of β-catenin, conducted by the Axin/GSK-3β/APC-constituted destruction complex. 22 However, phosphorylation of GSK-3β by protein kinase C may abolish GSK-3β′s action of phosphorylating βcatenin, leading to the cytoplasmic increase of β-catenin and its nuclear translocation, where β-catenin, together with TCF4 and LEF1, transactivates target gene transcription, e.g., oncogenic c-Myc and cyclin D1. 23 Compared with the control, UA decreased the protein expression of Wnt4, β-catenin, TCF4, LEF1, and phosphorylated GSK-3β in SW620 cells but reinforced GSK-3β and phosphorylated β-catenin protein expression (Figure 4B).…”

Section: Ursolic Acid Decreases the Wnt/β-catenin Signaling Cascade I...mentioning

confidence: 99%

Ursolic Acid Suppresses Colorectal Cancer by Down-Regulation of Wnt/β-Catenin Signaling Pathway Activity

Zhao

Tang

Qiu

et al. 2023

J. Agric. Food Chem.

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Overwhelming evidence points to an abnormally active Wnt/β-catenin signaling as a key player in colorectal cancer (CRC) pathogenesis. Ursolic acid (UA) is a pentacyclic triterpenoid that has been found in a broad variety of fruits, spices, and medicinal plants. UA has been shown to have potent bioactivity against a variety of cancers, including CRC, with the action mechanism obscure. Our study tried to learn more about the efficacy of UA on CRC and its functional mechanism amid the Wnt/β-catenin signaling cascade. We determined the efficacy of UA on CRC SW620 cells with respect to the proliferation, migration, clonality, apoptosis, cell cycle, and Wnt/β-catenin signaling cascade, with assessment of the effect of UA on normal colonic NCM460 cells. Also, the effects of UA on the tumor development, apoptosis, cell cycle, and Wnt/β-catenin signaling axis were evaluated after a subcutaneous SW620 xenograft tumor model was established in mice. In this work, we showed that UA drastically suppressed proliferation, migration, and clonality; induced apoptosis; and arrested the cell cycle at the G0/G1 phase of SW620 cells, without the influence on NCM460 cells, accompanied by weakened activity of the Wnt/β-catenin signaling pathway. Besides, UA markedly deterred the growth of the xenograft tumor, ameliorated pathological features, triggered apoptosis, and arrested the cell cycle in xenograft CRC tissue, by lessening the Wnt/β-catenin signaling cascade. Overall, UA may inhibit the malignant phenotype, induce apoptosis, and arrest the cell cycle of CRC, potentially by attenuating the Wnt/β-catenin signaling axis, providing insights into the mechanism for the potency of UA on CRC.

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Premise and peril of Wnt signaling activation through GSK-3β inhibition

Cited by 43 publications

References 44 publications

UXT-V1 contributes to the malignant phenotypes of colorectal cancer via GSK3β by activating Wnt/β-catenin pathway

UXT-V1 contributes to the malignant phenotypes of colorectal cancer via GSK3β by activating Wnt/β-catenin pathway

Suppression of preadipocyte determination by SOX4 limits white adipocyte hyperplasia in obesity

Ursolic Acid Suppresses Colorectal Cancer by Down-Regulation of Wnt/β-Catenin Signaling Pathway Activity

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